Publications by authors named "Fritz G Rathjen"

38 Publications

Early Days of Tenascin-R Research: Two Approaches Discovered and Shed Light on Tenascin-R.

Front Immunol 2020 8;11:612482. Epub 2021 Jan 8.

Department of Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

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http://dx.doi.org/10.3389/fimmu.2020.612482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820773PMC
June 2021

Early-Life Stress Regulates Cardiac Development through an IL-4-Glucocorticoid Signaling Balance.

Cell Rep 2020 11;33(7):108404

Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. Electronic address:

Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart.
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http://dx.doi.org/10.1016/j.celrep.2020.108404DOI Listing
November 2020

The CAR group of Ig cell adhesion proteins-Regulators of gap junctions?

Authors:
Fritz G Rathjen

Bioessays 2020 12 10;42(12):e2000031. Epub 2020 Nov 10.

Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Members of the CAR group of Ig-like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in the same knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT-IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and connexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE.
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http://dx.doi.org/10.1002/bies.202000031DOI Listing
December 2020

Sensory Neurons: The Formation of T-Shaped Branches Is Dependent on a cGMP-Dependent Signaling Cascade.

Neuroscientist 2021 02 23;27(1):47-57. Epub 2020 Apr 23.

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Axon bifurcation - a specific form of branching of somatosensory axons characterized by the splitting of the growth cone - is mediated by a cGMP-dependent signaling cascade composed of the extracellular ligand CNP (C-type natriuretic peptide), the transmembrane receptor guanylyl cyclase Npr2 (natriuretic peptide receptor 2), and the kinase cGKI (cGMP-dependent protein kinase I). In the absence of any one of these components, the formation of T-shaped axonal branches is impaired in neurons from DRGs (dorsal root ganglia), CSGs (cranial sensory ganglia) and MTNs (mesencephalic trigeminal neurons) in the murine spinal cord or hindbrain. Instead, axons from DRGs or from CSGs extend only either in an ascending or descending direction, while axons from MTNs either elongate within the hindbrain or extend via the trigeminal ganglion to the masseter muscles. Collateral formation from non-bifurcating stem axons is not affected by impaired cGMP signaling. Activation of Npr2 requires both binding of the ligand CNP as well as phosphorylation of serine and threonine residues at the juxtamembrane regions of the receptor. The absence of bifurcation results in an altered shape of termination fields of sensory afferents in the spinal cord and resulted in impaired noxious heat sensation and nociception whereas motor coordination appeared normal.
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http://dx.doi.org/10.1177/1073858420913844DOI Listing
February 2021

The cell adhesion protein CAR is a negative regulator of synaptic transmission.

Sci Rep 2019 05 1;9(1):6768. Epub 2019 May 1.

Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany.

The Coxsackievirus and adenovirus receptor (CAR) is essential for normal electrical conductance in the heart, but its role in the postnatal brain is largely unknown. Using brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes.
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http://dx.doi.org/10.1038/s41598-019-43150-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494904PMC
May 2019

The role of agrin, Lrp4 and MuSK during dendritic arborization and synaptogenesis in cultured embryonic CNS neurons.

Dev Biol 2019 01 29;445(1):54-67. Epub 2018 Oct 29.

Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, D-82152 Planegg-Martinsried, Germany. Electronic address:

The role of agrin, Lrp4 and MuSK, key organizers of neuromuscular synaptogenesis, in the developing CNS is only poorly understood. We investigated the role of these proteins in cultured mouse embryonic cortical neurons from wildtype and from Lrp4- and MuSK-deficient mice. Neurons from Lrp4-deficient mice had fewer but longer primary dendrites and a decreased density of puncta containing excitatory and inhibitory synapse-associated proteins. Neurons from MuSK-deficient mice had an altered dendritic branching pattern but no change in the density of puncta stained by antibodies against synapse-associated proteins. Transfection of TM-agrin compensated the dendritic branching deficits in Lrp4-deficient but not in MuSK-deficient neurons. TM-agrin transfection increased the density of excitatory synaptic puncta in MuSK-deficient but not in Lrp4-deficient mice and reduced the number of inhibitory synaptic puncta irrespective of MuSK and Lrp4 expression. Addition of purified soluble agrin to microisland cultures of cortical neurons revealed an Lrp4-dependent increase in the size and density of glutamatergic synaptic puncta and in mEPSC but not in mIPSC frequency and amplitude. Thus, agrin induced an Lrp4-independent increase in dendritic branch complexity, an Lrp4-dependent increase of excitatory synaptic puncta and an Lrp4- and MuSK-independent decrease in the density of puncta containing inhibitory synapse-associated proteins. These results establish selective roles for agrin, Lrp4 and MuSK during dendritogenesis and synaptogenesis in cultured CNS neurons.
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http://dx.doi.org/10.1016/j.ydbio.2018.10.017DOI Listing
January 2019

S-palmitoylation Is Required for the Control of Growth Cone Morphology of DRG Neurons by CNP-Induced cGMP Signaling.

Front Mol Neurosci 2018 24;11:345. Epub 2018 Sep 24.

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Genetic investigations have demonstrated that a specific form of axonal branching - the bifurcation of afferents from dorsal root ganglia (DRG), cranial sensory ganglia (CSG) and mesencephalic trigeminal neurons (MTN) - is regulated by a cGMP-dependent signaling pathway. This cascade is composed of the ligand C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and the cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, axons no longer bifurcate, instead they turn in either an ascending or a descending direction. To gain further mechanistic insights into the process of axon bifurcation we applied different cell culture approaches to decipher downstream activities of cGKI in somatosensory growth cones. We demonstrate that CNP induces an enlargement of DRG growth cones via cGKI which is considered as the priming step of axon bifurcation in the spinal cord. This growth cone remodeling was both blocked by pharmacological inhibitors of S-palmitoylation and potentiated by blocking de-palmitoylation. cGKI colocalizes with the palmitoylome and vesicular structures including the endoplasmic reticulum, early endosomes, lysosomes primarily in the central domain of the growth cone as well as with the Golgi apparatus at the level of the soma. Interestingly, an acyl-biotin-exchange chemistry-based screen indicated that 8pCPT-cGMP-induced signaling induces S-palmitoylation of a restricted pool of proteins in the DRG-derived cell line F11. Overall, our data indicate that CNP-induced cGMP signaling via cGKI affects growth cone morphology of somatosensory afferents. Moreover, it also suggests that S-palmitoylation might play a role in this process.
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http://dx.doi.org/10.3389/fnmol.2018.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166100PMC
September 2018

Regulation of the Natriuretic Peptide Receptor 2 (Npr2) by Phosphorylation of Juxtamembrane Serine and Threonine Residues Is Essential for Bifurcation of Sensory Axons.

J Neurosci 2018 11 24;38(45):9768-9780. Epub 2018 Sep 24.

Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany,

cGMP signaling elicited by activation of the transmembrane receptor guanylyl cyclase Npr2 (also known as guanylyl cyclase B) by the ligand CNP controls sensory axon bifurcation of DRG and cranial sensory ganglion (CSG) neurons entering the spinal cord or hindbrain, respectively. Previous studies have shown that Npr2 is phosphorylated on serine and threonine residues in its kinase homology domain (KHD). However, it is unknown whether phosphorylation of Npr2 is essential for axon bifurcation. Here, we generated a knock-in mouse line in which the seven regulatory serine and threonine residues in the KHD of Npr2 were substituted by alanine (Npr2-7A), resulting in a nonphosphorylatable enzyme. Real-time imaging of cGMP in DRG neurons with a genetically encoded fluorescent cGMP sensor or biochemical analysis of guanylyl cyclase activity in brain or lung tissue revealed the absence of CNP-induced cGMP generation in the mutant. Consequently, bifurcation of axons, but not collateral formation, from DRG or CSG in this mouse mutant was perturbed at embryonic and mature stages. In contrast, axon branching was normal in a mouse mutant in which constitutive phosphorylation of Npr2 is mimicked by a replacement of all of the seven serine and threonine sites by glutamic acid (Npr2-7E). Furthermore, we demonstrate that the mutation causes dwarfism as described for global Npr2 mutants. In conclusion, our studies provide strong evidence that phosphorylation of the seven serine and threonine residues in the KHD of Npr2 is an important regulatory element of Npr2-mediated cGMP signaling which affects physiological processes, such as axon bifurcation and bone growth. The branching of axons is a morphological hallmark of virtually all neurons. It allows an individual neuron to innervate different targets and to communicate with neurons located in different regions of the nervous system. The natriuretic peptide receptor 2 (Npr2), a transmembrane guanylyl cyclase, is essential for the initiation of bifurcation of sensory axons when entering the spinal cord or the hindbrain. By using two genetically engineered mouse lines, we show that phosphorylation of specific serine and threonine residues in juxtamembrane regions of Npr2 are required for its enzymatic activity and for axon bifurcation. These investigations might help to understand the regulation of Npr2 and its integration in intracellular signaling systems.
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http://dx.doi.org/10.1523/JNEUROSCI.0495-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222061PMC
November 2018

Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons.

EMBO J 2018 09 26;37(17). Epub 2018 Jul 26.

Developmental Biology/Signal Transduction Group, Max-Delbrueck-Centrum in the Helmholtz Association, Berlin, Germany

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low-affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin-positive (PV) interneurons. Nrg3 and ErbB4 are located pre- and postsynaptically, respectively, in excitatory synapses on PV interneurons Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short-term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4 interneurons and affects short-term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non-neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4 interneurons.
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http://dx.doi.org/10.15252/embj.201798858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120667PMC
September 2018

Loss of Axon Bifurcation in Mesencephalic Trigeminal Neurons Impairs the Maximal Biting Force in Npr2-Deficient Mice.

Front Cell Neurosci 2018 15;12:153. Epub 2018 Jun 15.

Max-Delbrück-Center, Berlin, Germany.

Bifurcation of axons from dorsal root ganglion (DRG) and cranial sensory ganglion (CSG) neurons is mediated by a cGMP-dependent signaling pathway composed of the ligand C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2 and the cGMP-dependent protein kinase I (cGKI). Here, we demonstrate that mesencephalic trigeminal neurons (MTN) which are the only somatosensory neurons whose cell bodies are located within the CNS co-express Npr2 and cGKI. Afferents of MTNs form Y-shaped branches in rhombomere 2 where the ligand CNP is expressed. Analyzing mouse mutants deficient for CNP or Npr2 we found that in the absence of CNP-induced cGMP signaling MTN afferents no longer bifurcate and instead extend either into the trigeminal root or caudally in the hindbrain. Since MTNs provide sensory information from jaw closing muscles and periodontal ligaments we measured the bite force of conditional mouse mutants of Npr2 ( ) that lack bifurcation of MTN whereas the bifurcation of trigeminal afferents is normal. Our study revealed that the maximal biting force of both sexes is reduced in mice as compared to their littermate controls. In conclusion sensory feedback mechanisms from jaw closing muscles or periodontal ligaments might be impaired in the absence of MTN axon bifurcation.
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http://dx.doi.org/10.3389/fncel.2018.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013911PMC
June 2018

Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade.

Int J Mol Sci 2018 Apr 24;19(5). Epub 2018 Apr 24.

Max-Delbrück-Center, Robert-Rössle-Str. 10, 13092 Berlin, Germany.

Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.
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http://dx.doi.org/10.3390/ijms19051266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983660PMC
April 2018

The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord.

Front Mol Neurosci 2018 8;11:19. Epub 2018 Feb 8.

Developmental Neurobiology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

A cGMP signaling cascade composed of C-type natriuretic peptide, the guanylyl cyclase receptor Npr2 and cGMP-dependent protein kinase I (cGKI) controls the bifurcation of sensory axons upon entering the spinal cord during embryonic development. However, the impact of axon bifurcation on sensory processing in adulthood remains poorly understood. To investigate the functional consequences of impaired axon bifurcation during adult stages we generated conditional mouse mutants of Npr2 and cGKI ( and ) that lack sensory axon bifurcation in the absence of additional phenotypes observed in the global knockout mice. Cholera toxin labeling in digits of the hind paw demonstrated an altered shape of sensory neuron termination fields in the spinal cord of conditional Npr2 mouse mutants. Behavioral testing of both sexes indicated that noxious heat sensation and nociception induced by chemical irritants are impaired in the mutants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are not affected. Recordings from C-fiber nociceptors in the hind limb skin showed that Npr2 function was not required to maintain normal heat sensitivity of peripheral nociceptors. Thus, the altered behavioral responses to noxious heat found in mice is not due to an impaired C-fiber function. Overall, these data point to a critical role of axonal bifurcation for the processing of pain induced by heat or chemical stimuli.
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http://dx.doi.org/10.3389/fnmol.2018.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809486PMC
February 2018

The IgCAM CLMP regulates expression of Connexin43 and Connexin45 in intestinal and ureteral smooth muscle contraction in mice.

Dis Model Mech 2018 02 22;11(2). Epub 2018 Feb 22.

Max-Delbrück-Center for Molecular Medicine, DE-13092 Berlin, Germany

CAR-like membrane protein (CLMP), an immunoglobulin cell adhesion molecule (IgCAM), has been implicated in congenital short-bowel syndrome in humans, a condition with high mortality for which there is currently no cure. We therefore studied the function of CLMP in a -deficient mouse model. Although we found that the levels of mRNAs encoding Connexin43 or Connexin45 were not or were only marginally affected, respectively, by deficiency, the absence of CLMP caused a severe reduction of both proteins in smooth muscle cells of the intestine and of Connexin43 in the ureter. Analysis of calcium signaling revealed a disordered cell-cell communication between smooth muscle cells, which in turn induced an impaired and uncoordinated motility of the intestine and the ureter. Consequently, insufficient transport of chyme and urine caused a fatal delay to thrive, a high rate of mortality, and provoked a severe hydronephrosis in CLMP knockouts. Neurotransmission and the capability of smooth muscle cells to contract in ring preparations of the intestine were not altered. Physical obstructions were not detectable and an overall normal histology in the intestine as well as in the ureter was observed, except for a slight hypertrophy of smooth muscle layers. Deletion of did not lead to a reduced length of the intestine as shown for the human gene but resulted in gut malrotations. In sum, the absence of CLMP caused functional obstructions in the intestinal tract and ureter by impaired peristaltic contractions most likely due to a lack of gap-junctional communication between smooth muscle cells.
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http://dx.doi.org/10.1242/dmm.032128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894946PMC
February 2018

The cell adhesion molecule BT-IgSF is essential for a functional blood-testis barrier and male fertility in mice.

J Biol Chem 2017 12 9;292(52):21490-21503. Epub 2017 Nov 9.

From the Department of Neurobiology and

The Ig-like cell adhesion molecule (IgCAM) BT-IgSF (brain- and testis-specific Ig superfamily protein) plays a major role in male fertility in mice. However, the molecular mechanism by which BT-IgSF supports fertility is unclear. Here, we found that it is localized in Sertoli cells at the blood-testis barrier (BTB) and at the apical ectoplasmic specialization. The absence of BT-IgSF in Sertoli cells in both global and conditional mouse mutants ( AMHCre and Rosa26CreERT2 lines) resulted in male infertility, atrophic testes with vacuolation, azoospermia, and spermatogenesis arrest. Although transcripts of junctional proteins such as connexin43, ZO-1, occludin, and claudin11 were up-regulated in the absence of BT-IgSF, the functional integrity of the BTB was impaired, as revealed by injection of a BTB-impermeable component into the testes under conditions. Disruption of the BTB coincided with mislocalization of connexin43, which was present throughout the seminiferous epithelium and not restricted to the BTB as in wild-type tissues, suggesting impaired cell-cell communication in the BT-IgSF-KO mice. Because EM images revealed a normal BTB structure between Sertoli cells in the BT-IgSF-KO mice, we conclude that infertility in these mice is most likely caused by a functionally impaired BTB. In summary, our results indicate that BT-IgSF is expressed at the BTB and is required for male fertility by supporting the functional integrity of the BTB.
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http://dx.doi.org/10.1074/jbc.RA117.000113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766970PMC
December 2017

Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease.

Mol Cell Neurosci 2017 06 18;81:32-40. Epub 2016 Nov 18.

Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany. Electronic address:

The immunoglobulin superfamily represents a diverse set of cell-cell contact proteins and includes well-studied members such as NCAM1, DSCAM, L1 or the contactins which are strongly expressed in the nervous system. In this review we put our focus on the biological function of a less understood subgroup of Ig-like proteins composed of CAR (coxsackievirus and adenovirus receptor), CLMP (CAR-like membrane protein) and BT-IgSF (brain and testis specific immunoglobulin superfamily). The CAR-related proteins are type I transmembrane proteins containing an N-terminal variable (V-type) and a membrane proximal constant (C2-type) Ig domain in their extracellular region which are implicated in homotypic adhesion. They are highly expressed during embryonic development in a variety of tissues including the nervous system whereby in adult stages the protein level of CAR and CLMP decreases, only BT-IgSF expression increases within age. CAR-related proteins are concentrated at specialized cell-cell communication sites such as gap or tight junctions and are present at the plasma membrane in larger protein complexes. Considerable progress has been made on the molecular structure and interactions of CAR while research on CLMP and BT-IgSF is at an early stage. Studies on mouse mutants revealed biological functions of CAR in the heart and for CLMP in the gastrointestinal and urogenital systems. Furthermore, CAR and BT-IgSF appear to regulate synaptic function in the hippocampus.
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http://dx.doi.org/10.1016/j.mcn.2016.11.009DOI Listing
June 2017

Dorsal root ganglion axon bifurcation tolerates increased cyclic GMP levels: the role of phosphodiesterase 2A and scavenger receptor Npr3.

Eur J Neurosci 2016 12 3;44(12):2991-3000. Epub 2016 Nov 3.

Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, 13092, Berlin, Germany.

A cyclic GMP (cGMP) signaling pathway, comprising C-type natriuretic peptide (CNP), its guanylate cyclase receptor Npr2, and cGMP-dependent protein kinase I, is critical for the bifurcation of dorsal root ganglion (DRG) and cranial sensory ganglion axons when entering the mouse spinal cord and the hindbrain respectively. However, the identity and functional relevance of phosphodiesterases (PDEs) that degrade cGMP in DRG neurons are not completely understood. Here, we asked whether regulation of the intracellular cGMP concentration by PDEs modulates the branching of sensory axons. Real-time imaging of cGMP with a genetically encoded fluorescent cGMP sensor, RT-PCR screens, in situ hybridization, and immunohistology combined with the analysis of mutant mice identified PDE2A as the major enzyme for the degradation of CNP-induced cGMP in embryonic DRG neurons. Tracking of PDE2A-deficient DRG sensory axons in conjunction with cGMP measurements indicated that axon bifurcation tolerates increased cGMP concentrations. As we found that the natriuretic peptide scavenger receptor Npr3 is expressed by cells associated with dorsal roots but not in DRG neurons itself at early developmental stages, we analyzed axonal branching in the absence of Npr3. In Npr3-deficient mice, the majority of sensory axons showed normal bifurcation, but a small population of axons (13%) was unable to form T-like branches and generated turns in rostral or caudal directions only. Taken together, this study shows that sensory axon bifurcation is insensitive to increases of CNP-induced cGMP levels and Npr3 does not have an important scavenging function in this axonal system.
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http://dx.doi.org/10.1111/ejn.13434DOI Listing
December 2016

The IgCAMs CAR, BT-IgSF, and CLMP: structure, function, and diseases.

Adv Neurobiol 2014 ;8:21-45

The coxsackie-adenovirus receptor (CAR) is the prototype of a small subfamily of IgCAMs composed of CAR itself, CLMP, BT-IgSF, ESAM, CTX, and A33. These six proteins are composed of one V-set and one C2-set Ig domains and a single transmembrane helix followed by a cytoplasmic stretch. They are localized in several tissues and organs and--except for ESAM, CTX, and A33--are expressed in the developing brain. CAR becomes downregulated at early postnatal stages and is absent from the adult brain. CAR, CLMP, and BT-IgSF mediate homotypic aggregation. Interestingly, cell adhesion experiments, binding studies, and crystallographic investigations on the extracellular domain reveal a flexible ectodomain for CAR that mediates homophilic and heterophilic binding. CAR has been extensively investigated in the context of gene therapy and diseases, while research on BT-IgSF and CLMP is at an early stage. Several mouse models as well as studies on patient tissues revealed an essential role for CAR in (1) the development of cardiac, renal, lymphatic, and intestinal tissue; (2) muscle pathology, remodeling, and regeneration; (3) tumor genesis/suppression and metastatic progression; and (4) in virus-mediated infections and gene therapy. Although the in vivo function of CAR in the brain has not been solved its developmentally regulated expression pattern in the brain as well as its function as CAM suggests that CAR might be implicated in neuronal network formation.
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http://dx.doi.org/10.1007/978-1-4614-8090-7_2DOI Listing
October 2014

Bifurcation of axons from cranial sensory neurons is disabled in the absence of Npr2-induced cGMP signaling.

J Neurosci 2014 Jan;34(3):737-47

Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.

Axonal branching is a prerequisite for the establishment of complex neuronal circuits and their capacity for parallel information processing. Previously, we have identified a cGMP signaling pathway composed of the ligand C-type natriuretic peptide (CNP), its receptor, the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), and the cGMP-dependent kinase Iα (cGKIα) that regulates axon bifurcation of dorsal root ganglion (DRG) neurons in the spinal cord. Now we asked whether this cascade also controls axon bifurcation elsewhere in the nervous system. An Npr2-lacZ reporter mouse line was generated to clarify the pattern of the CNP receptor expression. It was found that during the period of axonal outgrowth, Npr2 and cGKIα were strongly labeled in neurons of all cranial sensory ganglia (gV, gVII, gVIII, gIX, and gX). In addition, strong complementary expression of CNP was detected in the hindbrain at the entry zones of sensory afferents. To analyze axon branching in individual Npr2-positive neurons, we generated a mouse mutant expressing a tamoxifen-inducible variant of Cre recombinase expressed under control of the Npr2-promoter (Npr2-CreER(T2)). After crossing this strain with conditional reporter mouse lines, we revealed that the complete absence of Npr2 activity indeed prohibited the bifurcation of cranial sensory axons in their entrance region. Consequently, axons only turned in either an ascending or descending direction, while collateral formation and growth of the peripheral arm was not affected. These findings indicate that in neurons of the cranial sensory ganglia, as in DRG neurons, cGMP signals are necessary for the execution of an axonal bifurcation program.
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http://dx.doi.org/10.1523/JNEUROSCI.4183-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608349PMC
January 2014

Changes in neural network homeostasis trigger neuropsychiatric symptoms.

J Clin Invest 2014 Feb 16;124(2):696-711. Epub 2014 Jan 16.

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.
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http://dx.doi.org/10.1172/JCI71472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904623PMC
February 2014

Retinal pigment epithelium protein of 65 kDA gene-linked retinal degeneration is not modulated by chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C/ chondroitin sulfate proteoglycan 5.

Mol Vis 2013 16;19:2312-20. Epub 2013 Nov 16.

Institute for Research in Ophthalmology, Sion, Switzerland ; Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland.

Purpose: To analyze in vivo the function of chicken acidic leucine-rich epidermal growth factor-like domain containing brain protein/Neuroglycan C (gene symbol: Cspg5) during retinal degeneration in the Rpe65⁻/⁻ mouse model of Leber congenital amaurosis.

Methods: We resorted to mice with targeted deletions in the Cspg5 and retinal pigment epithelium protein of 65 kDa (Rpe65) genes (Cspg5⁻/⁻/Rpe65⁻/⁻). Cone degeneration was assessed with cone-specific peanut agglutinin staining. Transcriptional expression of rhodopsin (Rho), S-opsin (Opn1sw), M-opsin (Opn1mw), rod transducin α subunit (Gnat1), and cone transducin α subunit (Gnat2) genes was assessed with quantitative PCR from 2 weeks to 12 months. The retinal pigment epithelium (RPE) was analyzed at P14 with immunodetection of the retinol-binding protein membrane receptor Stra6.

Results: No differences in the progression of retinal degeneration were observed between the Rpe65⁻/⁻ and Cspg5⁻/⁻/Rpe65⁻/⁻ mice. No retinal phenotype was detected in the late postnatal and adult Cspg5⁻/⁻ mice, when compared to the wild-type mice.

Conclusions: Despite the previously reported upregulation of Cspg5 during retinal degeneration in Rpe65⁻/⁻ mice, no protective effect or any involvement of Cspg5 in disease progression was identified.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834887PMC
March 2014

Impaired presynaptic function and elimination of synapses at premature stages during postnatal development of the cerebellum in the absence of CALEB (CSPG5/neuroglycan C).

Eur J Neurosci 2013 Nov 25;38(9):3270-80. Epub 2013 Jul 25.

Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13092, Berlin, Germany.

Chicken acidic leucine-rich EGF-like domain-containing brain protein (CALEB), also known as chondroitin sulfate proteoglycan (CSPG)5 or neuroglycan C, is a neural chondroitin sulfate-containing and epidermal growth factor (EGF)-domain-containing transmembrane protein that is implicated in synaptic maturation. Here, we studied the role of CALEB within the developing cerebellum. Adult CALEB-deficient mice displayed impaired motor coordination in Rota-Rod experiments. Analysis of the neuronal connectivity of Purkinje cells by patch-clamp recordings demonstrated impairments of presynaptic maturation of inhibitory synapses. GABAergic synapses on Purkinje cells revealed decreased evoked amplitudes, altered paired-pulse facilitation and reduced depression after repetitive stimulation at early postnatal but not at mature stages. Furthermore, the elimination of supernumerary climbing fiber synapses on Purkinje cells was found to occur at earlier developmental stages in the absence of CALEB. For example, at postnatal day 8 in wild-type mice, 54% of Purkinje cells had three or more climbing fiber synapses in contrast to mutants where this number was decreased to less than 25%. The basic properties of the climbing fiber Purkinje cell synapse remained unaffected. Using Sholl analysis of dye-injected Purkinje cells we revealed that the branching pattern of the dendritic tree of Purkinje cells was not impaired in CALEB-deficient mice. The alterations observed by patch-clamp recordings correlated with a specific pattern and timing of expression of CALEB in Purkinje cells, i.e. it is dynamically regulated during development from a high chondroitin sulfate-containing form to a non-chondroitin sulfate-containing form. Thus, our results demonstrated an involvement of CALEB in the presynaptic differentiation of cerebellar GABAergic synapses and revealed a new role for CALEB in synapse elimination in Purkinje cells.
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http://dx.doi.org/10.1111/ejn.12313DOI Listing
November 2013

A genetic strategy for the analysis of individual axon morphologies in cGMP signalling mutant mice.

Methods Mol Biol 2013 ;1020:193-204

Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.

One of the many physiological functions of cyclic guanosine 3',5' monophosphate (cGMP) signalling is the regulation of a specific mode of axonal branching. The bifurcation of axons from dorsal root ganglion (DRG) neurons at the dorsal root entry zone of the embryonic spinal cord is triggered by a cGMP -signalling pathway comprising the ligand C-type natriuretic peptide (CNP), the cGMP-producing natriuretic peptide receptor 2 (Npr2), and the cGMP-dependent protein kinase Iα (cGKIα). Absence of any of these components causes a loss of bifurcation and sensory axons instead only turn in either a rostral or a caudal direction. In this chapter we describe a genetic strategy to study the impact of cGMP signalling on the arborization of individual DRG neurons in mice. Expression of an alkaline phosphatase (AP) reporter is selectively induced in Npr2-positive DRG neurons by tamoxifen-dependent activation of a Cre -recombinase under the control of the Npr2 promoter. This approach might also be employed for the analysis of axonal branching in neuronal subsets expressing Npr2 elsewhere in the nervous system.
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http://dx.doi.org/10.1007/978-1-62703-459-3_12DOI Listing
December 2013

Regulation of adhesion by flexible ectodomains of IgCAMs.

Neurochem Res 2013 Jun 9;38(6):1092-9. Epub 2012 Oct 9.

Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.

To perform their diverse biological functions the adhesion activities of the cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) might be regulated by local clustering, proteolytical shedding of their ectodomains or rapid recycling to and from the plasma membrane. Another form of regulation of adhesion might be obtained through flexible ectodomains of IgCAMs which adopt distinct conformations and which in turn modulate their adhesion activity. Here, we discuss variations in the conformation of the extracellular domains of CEACAM1 and CAR that might influence their binding and signaling activities. Furthermore, we concentrate on alternative splicing of single domains and short segments in the extracellular regions of L1 subfamily members that might affect the organization of the N-terminal located Ig-like domains. In particular, we discuss variations of the linker sequence between Ig-like domains 2 and 3 (D2 and D3) that is required for the horseshoe conformation.
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http://dx.doi.org/10.1007/s11064-012-0888-9DOI Listing
June 2013

Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype.

PLoS One 2012 23;7(7):e41537. Epub 2012 Jul 23.

MRC Mammalian Genetics Unit, Harwell, Oxfordshire, United Kingdom.

To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041537PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402391PMC
November 2012

DiI-labeling of DRG neurons to study axonal branching in a whole mount preparation of mouse embryonic spinal cord.

J Vis Exp 2011 Dec 13(58). Epub 2011 Dec 13.

Developmental Neurobiology, Max Delbrück Center for Molecular Medicine.

Here we present a technique to label the trajectories of small groups of DRG neurons into the embryonic spinal cord by diffusive staining using the lipophilic tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). The comparison of axonal pathways of wild-type with those of mouse lines in which genes are mutated allows testing for a functional role of candidate proteins in the control of axonal branching which is an essential mechanism in the wiring of the nervous system. Axonal branching enables an individual neuron to connect with multiple targets, thereby providing the physical basis for the parallel processing of information. Ramifications at intermediate target regions of axonal growth may be distinguished from terminal arborization. Furthermore, different modes of axonal branch formation may be classified depending on whether branching results from the activities of the growth cone (splitting or delayed branching) or from the budding of collaterals from the axon shaft in a process called interstitial branching (Fig. 1). The central projections of neurons from the DRG offer a useful experimental system to study both types of axonal branching: when their afferent axons reach the dorsal root entry zone (DREZ) of the spinal cord between embryonic days 10 to 13 (E10-E13) they display a stereotyped pattern of T- or Y-shaped bifurcation. The two resulting daughter axons then proceed in rostral or caudal directions, respectively, at the dorsolateral margin of the cord and only after a waiting period collaterals sprout from these stem axons to penetrate the gray matter (interstitial branching) and project to relay neurons in specific laminae of the spinal cord where they further arborize (terminal branching). DiI tracings have revealed growth cones at the dorsal root entry zone of the spinal cord that appeared to be in the process of splitting suggesting that bifurcation is caused by splitting of the growth cone itself (Fig. 2), however, other options have been discussed as well. This video demonstrates first how to dissect the spinal cord of E12.5 mice leaving the DRG attached. Following fixation of the specimen tiny amounts of DiI are applied to DRG using glass needles pulled from capillary tubes. After an incubation step, the labeled spinal cord is mounted as an inverted open-book preparation to analyze individual axons using fluorescence microscopy.
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http://dx.doi.org/10.3791/3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369642PMC
December 2011

Signalling mechanisms regulating axonal branching in vivo.

Bioessays 2010 Nov 8;32(11):977-85. Epub 2010 Sep 8.

Max-Delbrück-Centre for Molecular Medicine, Berlin, Germany.

Identification of the molecular mechanisms underlying axonal branching in vivo has begun in several neuronal systems, notably the projections formed by dorsal root ganglion (DRG) neurons or retinal ganglion cells (RGC). cGMP signalling is essential for sensory axon bifurcation at the spinal cord, whereas brain-derived neurotrophic factor (BDNF) and ephrinA signalling establish position-dependent branching of RGC axons. In the latter system, the degradation of specific signalling components, via the ubiquitin-proteasome system, may provide an additional mechanism involved in axon branching of RGC. The process of arborisation is essential for neurons to innervate multiple targets and to build topographic maps. The various forms of branching found in different types of neurons are regulated by distinct signalling pathways activated by multiple extracellular cues in addition to axonal guidance factors. These signalling cascades, together with transcriptional programs, most likely interact and trigger the polymerisation or depolymerisation of the actin and tubulin cytoskeleton to regulate branching.
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http://dx.doi.org/10.1002/bies.201000054DOI Listing
November 2010

L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.

Neurobiol Dis 2010 Oct 31;40(1):222-37. Epub 2010 May 31.

Institut für Anatomie und Zellbiologie, Universität Freiburg, 79104 Freiburg, Germany.

Mutations in the human L1CAM gene cause neurodevelopmental disorders collectively referred to as L1 syndrome. Here, we investigated cellular pathomechanisms underlying two L1 syndrome mutations, R184Q and W1036L. We demonstrate that these mutations cause partial endoplasmic reticulum (ER) retention of L1, reduce L1 cell surface expression, but do not induce ER stress in neuronal NSC-34 cells. We provide evidence that surface trafficking of mutated L1 is affected by defective sorting to ER exit sites and attenuated ER export. However, in differentiated neuronal cultures and long-term cultured hippocampal slices, the L1-R184Q protein is restricted to cell bodies, whereas L1-W1036L also aberrantly localizes to dendrites. These trafficking defects preclude axonal targeting of L1, thereby affecting L1-mediated axon growth and arborization. Our results indicate that L1 syndrome mutations impair neuronal L1 function at different levels, firstly by attenuating ER export and secondly by interfering with polarized neuronal trafficking.
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http://dx.doi.org/10.1016/j.nbd.2010.05.029DOI Listing
October 2010

The coxsackievirus-adenovirus receptor reveals complex homophilic and heterophilic interactions on neural cells.

J Neurosci 2010 Feb;30(8):2897-910

Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.

The coxsackievirus-adenovirus receptor (CAR) is a member of the Ig superfamily strongly expressed in the developing nervous system. Our histological investigations during development reveal an initial uniform distribution of CAR on all neural cells with a concentration on membranes that face the margins of the nervous system (e.g., the basal laminae and the ventricular side). At more advanced stages, CAR becomes downregulated and restricted to specific regions including areas rich in axonal and dendritic surfaces. To study the function of CAR on neural cells, we used the fiber knob of the adenovirus, extracellular CAR domains, blocking antibodies to CAR, as well as CAR-deficient neural cells. Blocking antibodies were found to inhibit neurite extension in retina organ and retinal explant cultures, whereas the application of the recombinant fiber knob of the adenovirus subtype Ad2 or extracellular CAR domains promoted neurite extension and adhesion to extracellular matrices. We observed a promiscuous interaction of CAR with extracellular matrix glycoproteins, which was deduced from analytical ultracentrifugation experiments, affinity chromatography, and adhesion assays. The membrane proximal Ig domain of CAR, termed D2, was found to bind to a fibronectin fragment, including the heparin-binding domain 2, which promotes neurite extension of wild type, but not of CAR-deficient neural cells. In contrast to heterophilic interactions, homophilic association of CAR involves both Ig domains, as was revealed by ultracentrifugation, chemical cross-linking, and adhesion studies. The results of these functional and binding studies are correlated to a U-shaped homodimer of the complete extracellular domains of CAR detected by x-ray crystallography.
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http://dx.doi.org/10.1523/JNEUROSCI.5725-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633923PMC
February 2010

C-type natriuretic peptide (CNP) is a bifurcation factor for sensory neurons.

Proc Natl Acad Sci U S A 2009 Sep 17;106(39):16847-52. Epub 2009 Sep 17.

Department of Developmental Neurobiology, Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, Berlin, Germany.

Neuronal circuits are shaped during development by the coordinated action of guidance factors and signals that regulate axonal branching. Unlike guidance cues, the molecules and signaling cascades that underlie axonal branching remain to be resolved. Here we show that the secreted molecule C-type natriuretic peptide (CNP) induces a cGMP signaling cascade via its receptor particulate guanylyl cyclase Npr2 which is essential for sensory axon bifurcation at the dorsal root entry zone (DREZ) of the spinal cord. In contrast, another form of sensory axon branching-collateral formation-is not affected by this pathway. We also demonstrate that cGMP signaling via the nitric oxide-stimulated soluble guanylyl cyclase system (NO-GC) is dispensable for sensory axon branching. Functionally, the bifurcation error in CNP mutant mice is maintained at mature stages and results in a reduced input on secondary neurons as detected by patch-clamp recordings.
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http://dx.doi.org/10.1073/pnas.0906571106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757798PMC
September 2009

Early maturation of GABAergic synapses in mouse retinal ganglion cells.

Int J Dev Neurosci 2008 Apr 15;26(2):233-8. Epub 2007 Dec 15.

Developmental Neurobiology, Max-Delbrück-Center, Robert-Rössle-Str. 10, 13092 Berlin, Germany.

This study was aimed to characterize the earliest phases of synapse development in mouse retinal ganglion cells (RGCs) by recording spontaneous postsynaptic currents (PSCs). First PSCs were detected at embryonic day 17 and completely suppressed by bicuculline, demonstrating their GABAergic nature. Starting from postnatal day 3 a small fraction of RGCs had rapidly decaying, most likely glutamatergic currents. The present results suggest that functional GABAergic synapses with RGCs appear before birth and that GABAergic synaptic transmission precedes that of glutamate in the retina. In this early period GABA acts in a depolarizing manner and takes over an excitatory function.
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http://dx.doi.org/10.1016/j.ijdevneu.2007.12.001DOI Listing
April 2008
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