Publications by authors named "Gordon Fishell"

21 Publications

  • Page 1 of 1

Author Correction: A community-based transcriptomics classification and nomenclature of neocortical cell types.

Nat Neurosci 2021 Apr;24(4):612

Allen Institute for Brain Science, Seattle, WA, USA.

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http://dx.doi.org/10.1038/s41593-020-00779-0DOI Listing
April 2021

Cellular birthdate predicts laminar and regional cholinergic projection topography in the forebrain.

Elife 2020 12 23;9. Epub 2020 Dec 23.

Department of Neurobiology, Harvard Medical School, Boston, United States.

The basal forebrain cholinergic system projects broadly throughout the cortex and constitutes a critical source of neuromodulation for arousal and attention. Traditionally, this system was thought to function diffusely. However, recent studies have revealed a high degree of spatiotemporal specificity in cholinergic signaling. How the organization of cholinergic afferents confers this level of precision remains unknown. Here, using intersectional genetic fate mapping, we demonstrate that cholinergic fibers within the mouse cortex exhibit remarkable laminar and regional specificity and that this is organized in accordance with cellular birthdate. Strikingly, birthdated cholinergic projections within the cortex follow an inside-out pattern of innervation. While early born cholinergic populations target deep layers, late born ones innervate superficial laminae. We also find that birthdate predicts cholinergic innervation patterns within the amygdala, hippocampus, and prefrontal cortex. Our work reveals previously unappreciated specificity within the cholinergic system and the developmental logic by which these circuits are assembled.
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http://dx.doi.org/10.7554/eLife.63249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758062PMC
December 2020

Publisher Correction: A community-based transcriptomics classification and nomenclature of neocortical cell types.

Nat Neurosci 2021 Apr;24(4):613

Allen Institute for Brain Science, Seattle, WA, USA.

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http://dx.doi.org/10.1038/s41593-020-00768-3DOI Listing
April 2021

Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex.

Elife 2020 10 9;9. Epub 2020 Oct 9.

Center for Neural Science, New York University, New York, United States.

Connections from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) regulate cognition, emotion, and memory. These functions are also tightly controlled by inhibitory networks in the PFC, whose disruption is thought to contribute to mental health disorders. However, relatively little is known about how the vHPC engages different populations of interneurons in the PFC. Here we use slice physiology and optogenetics to study vHPC-evoked feed-forward inhibition in the mouse PFC. We first show that cholecystokinin (CCK+), parvalbumin (PV+), and somatostatin (SOM+) expressing interneurons are prominent in layer 5 (L5) of infralimbic PFC. We then show that vHPC inputs primarily activate CCK+ and PV+ interneurons, with weaker connections onto SOM+ interneurons. CCK+ interneurons make stronger synapses onto pyramidal tract (PT) cells over nearby intratelencephalic (IT) cells. However, CCK+ inputs undergo depolarization-induced suppression of inhibition (DSI) and CB1 receptor modulation only at IT cells. Moreover, vHPC-evoked feed-forward inhibition undergoes DSI only at IT cells, confirming a central role for CCK+ interneurons. Together, our findings show how vHPC directly engages multiple populations of inhibitory cells in deep layers of the infralimbic PFC, highlighting unexpected roles for both CCK+ interneurons and endocannabinoid modulation in hippocampal-prefrontal communication.
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http://dx.doi.org/10.7554/eLife.55267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609047PMC
October 2020

A community-based transcriptomics classification and nomenclature of neocortical cell types.

Nat Neurosci 2020 12;23(12):1456-1468

Allen Institute for Brain Science, Seattle, WA, USA.

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.
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http://dx.doi.org/10.1038/s41593-020-0685-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683348PMC
December 2020

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Cell 2020 06 2;181(7):1547-1565.e15. Epub 2020 Jun 2.

Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman Medical Center, New York, NY 10016, USA; Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address:

Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca-permeable AMPA receptor upregulation, L-type Ca channel activation, enhanced spine Ca transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.cell.2020.05.013DOI Listing
June 2020

Paradoxical network excitation by glutamate release from VGluT3 GABAergic interneurons.

Elife 2020 02 13;9. Epub 2020 Feb 13.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.

In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCKVGluT3INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCKVGluT3INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCKVGluT3INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCKVGluT3INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCKVGluT3INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.
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http://dx.doi.org/10.7554/eLife.51996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039679PMC
February 2020

Characterizing chromatin landscape from aggregate and single-cell genomic assays using flexible duration modeling.

Nat Commun 2020 02 6;11(1):747. Epub 2020 Feb 6.

Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, 10010, USA.

ATAC-seq has become a leading technology for probing the chromatin landscape of single and aggregated cells. Distilling functional regions from ATAC-seq presents diverse analysis challenges. Methods commonly used to analyze chromatin accessibility datasets are adapted from algorithms designed to process different experimental technologies, disregarding the statistical and biological differences intrinsic to the ATAC-seq technology. Here, we present a Bayesian statistical approach that uses latent space models to better model accessible regions, termed ChromA. ChromA annotates chromatin landscape by integrating information from replicates, producing a consensus de-noised annotation of chromatin accessibility. ChromA can analyze single cell ATAC-seq data, correcting many biases generated by the sparse sampling inherent in single cell technologies. We validate ChromA on multiple technologies and biological systems, including mouse and human immune cells, establishing ChromA as a top performing general platform for mapping the chromatin landscape in different cellular populations from diverse experimental designs.
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http://dx.doi.org/10.1038/s41467-020-14497-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004981PMC
February 2020

Activity of Prefrontal Neurons Predict Future Choices during Gambling.

Neuron 2019 01 6;101(1):152-164.e7. Epub 2018 Dec 6.

Center for Brain Research, Division of Cognitive Neurobiology, Medical University Vienna, Vienna, Austria. Electronic address:

Neuronal signals in the prefrontal cortex have been reported to predict upcoming decisions. Such activity patterns are often coupled to perceptual cues indicating correct choices or values of different options. How does the prefrontal cortex signal future decisions when no cues are present but when decisions are made based on internal valuations of past experiences with stochastic outcomes? We trained rats to perform a two-arm bandit-task, successfully adjusting choices between certain-small or possible-big rewards with changing long-term advantages. We discovered specialized prefrontal neurons, whose firing during the encounter of no-reward predicted the subsequent choice of animals, even for unlikely or uncertain decisions and several seconds before choice execution. Optogenetic silencing of the prelimbic cortex exclusively timed to encounters of no reward, provoked animals to excessive gambling for large rewards. Firing of prefrontal neurons during outcome evaluation signals subsequent choices during gambling and is essential for dynamically adjusting decisions based on internal valuations.
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http://dx.doi.org/10.1016/j.neuron.2018.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318061PMC
January 2019

Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon.

Development 2018 01 9;145(1). Epub 2018 Jan 9.

Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400,005, India

During forebrain development, a telencephalic organizer called the cortical hem is crucial for inducing hippocampal fate in adjacent cortical neuroepithelium. How the hem is restricted to its medial position is therefore a fundamental patterning issue. Here, we demonstrate that - interactions are crucial for the formation of the hem. Loss of either gene causes a region of the cortical neuroepithelium to transform into hem. We show that FOXG1 regulates expression in the cortical primordium. In the absence of , the presence of is sufficient to suppress hem fate, and hippocampal markers appear selectively in -expressing regions. FOXG1 also restricts the temporal window in which loss of results in a transformation of cortical primordium into hem. Therefore, and form a genetic hierarchy in the spatiotemporal regulation of cortical hem specification and positioning, and together ensure the normal development of this hippocampal organizer.
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http://dx.doi.org/10.1242/dev.154583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825872PMC
January 2018

FGF-Dependent, Context-Driven Role for FRS Adapters in the Early Telencephalon.

J Neurosci 2017 06 8;37(23):5690-5698. Epub 2017 May 8.

Department of Neuroscience and

FGF signaling, an important component of intercellular communication, is required in many tissues throughout development to promote diverse cellular processes. Whether FGF receptors (FGFRs) accomplish such varied tasks in part by activating different intracellular transducers in different contexts remains unclear. Here, we used the developing mouse telencephalon as an example to study the role of the FRS adapters FRS2 and FRS3 in mediating the functions of FGFRs. Using tissue-specific and germline mutants, we examined the requirement of Frs genes in two FGFR-dependent processes. We found that and are together required for the differentiation of a subset of medial ganglionic eminence (MGE)-derived neurons, but are dispensable for the survival of early telencephalic precursor cells, in which any one of three FGFRs (FGFR1, FGFR2, or FGFR3) is sufficient for survival. Although FRS adapters are dispensable for ERK-1/2 activation, they are required for AKT activation within the subventricular zone of the developing MGE. Using an FRS2,3-binding site mutant of , we established that FRS adapters are necessary for mediating most or all FGFR1 signaling, not only in MGE differentiation, but also in cell survival, implying that other adapters mediate at least in part the signaling from FGFR2 and FGFR3. Our study provides an example of a contextual role for an intracellular transducer and contributes to our understanding of how FGF signaling plays diverse developmental roles. FGFs promote a range of developmental processes in many developing tissues and at multiple developmental stages. The mechanisms underlying this multifunctionality remain poorly defined Using telencephalon development as an example, we show here that FRS adapters exhibit some selectivity in their requirement for mediating FGF receptor (FGFR) signaling and activating downstream mediators that depend on the developmental process, with a requirement in neuronal differentiation but not cell survival. Differential engagement of FRS and non-FRS intracellular adapters downstream of FGFRs could therefore in principle explain how FGFs play several distinct roles in other developing tissues and developmental stages.
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http://dx.doi.org/10.1523/JNEUROSCI.2931-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469306PMC
June 2017

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling.

Proc Natl Acad Sci U S A 2014 Jul 7;111(29):E2987-95. Epub 2014 Jul 7.

Departments of Neuroscience and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461;

In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss- and gain-of-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.
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http://dx.doi.org/10.1073/pnas.1320401111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115557PMC
July 2014

Interneuron cell types are fit to function.

Nature 2014 Jan;505(7483):318-26

NYU Langone Medical Center, First Avenue, Smilow Research Building, New York 10016, USA.

Understanding brain circuits begins with an appreciation of their component parts - the cells. Although GABAergic interneurons are a minority population within the brain, they are crucial for the control of inhibition. Determining the diversity of these interneurons has been a central goal of neurobiologists, but this amazing cell type has so far defied a generalized classification system. Interneuron complexity within the telencephalon could be simplified by viewing them as elaborations of a much more finite group of developmentally specified cardinal classes that become further specialized as they mature. Our perspective emphasizes that the ultimate goal is to dispense with classification criteria and directly define interneuron types by function.
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http://dx.doi.org/10.1038/nature12983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349583PMC
January 2014

Hurricane Sandy: After the deluge.

Authors:
Gordon Fishell

Nature 2013 Apr;496(7446):421-2

Neuroscience Institute, New York University, New York, NY 10016, USA.

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http://dx.doi.org/10.1038/496421aDOI Listing
April 2013

Pioneer glutamatergic cells develop into a morpho-functionally distinct population in the juvenile CA3 hippocampus.

Nat Commun 2012 ;3:1316

Inserm Unité 901, Marseille 13009, France.

The developing CA3 hippocampus is comprised by highly connected hub neurons that are particularly effective in achieving network synchronization. Functional hub neurons were shown to be exclusively GABAergic, suggesting that the contribution of glutamatergic neurons to physiological synchronization processes at early postnatal stages is minimal. However, without fast GABAergic transmission, a different situation may prevail. In the adult CA3, blocking fast GABAergic transmission induces the generation of network bursts that can be triggered by the stimulation of single pyramidal neurons. Here we revisit the network function of CA3 glutamatergic neurons from a developmental viewpoint, without fast GABAergic transmission. We uncover a sub-population of early-generated glutamatergic neurons that impacts network dynamics when stimulated in the juvenile hippocampus. Additionally, this population displays characteristic morpho-physiological features in the juvenile and adult hippocampus. Therefore, the apparently homogeneous glutamatergic cell population likely displays a morpho-functional diversity rooted in temporal embryonic origins.
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http://dx.doi.org/10.1038/ncomms2318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535425PMC
June 2013

Functional adaptation of cortical interneurons to attenuated activity is subtype-specific.

Front Neural Circuits 2012 24;6:66. Epub 2012 Sep 24.

Smilow Neuroscience, NYU Langone Medical Center, Neuroscience Institute New York City, NY, USA.

Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE)-derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin-expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability.
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http://dx.doi.org/10.3389/fncir.2012.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3449283PMC
October 2012

Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.

Nat Neurosci 2012 Mar 25;15(5):700-2. Epub 2012 Mar 25.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.
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http://dx.doi.org/10.1038/nn.3079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380241PMC
March 2012

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.

Dev Neurobiol 2011 Jan;71(1):45-61

Smilow Neuroscience Program, Smilow Research Center, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA.

An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for ∼40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents ∼30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for ∼30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts.
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http://dx.doi.org/10.1002/dneu.20853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556905PMC
January 2011

Previews. Inhibition as a transplant-mediated therapy: a new paradigm for treating Parkinson's?

Cell Stem Cell 2010 Mar;6(3):184-5

Smilow Neuroscience Program and the Department Cell Biology, Smilow Research Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA.

In this issue of Cell Stem Cell,Martínez-Cerdeño and colleagues (2010) transplant interneuron precursors from the MGE into the striatum of a rat model of Parkinson's disease and observe a 5% increase in the endogenous GABAergic interneuron population resulting in behavioral benefits in both lesioned and wild-type animals.
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http://dx.doi.org/10.1016/j.stem.2010.02.003DOI Listing
March 2010

Perspectives on the developmental origins of cortical interneuron diversity.

Authors:
Gordon Fishell

Novartis Found Symp 2007 ;288:21-35; discussion 35-44, 96-8

Smilow Neuroscience Program, Department of Cell Biology, Floor Smilow Research Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA.

Cortical GABAergic interneurons in mice are largely derived from the subpallium. Work from our laboratory and others over the past five years has demonstrated that a developmental logic in space and time underlies the emergence of specific cortical interneuronal subtypes. Following on from the seminal work of the Rubenstein laboratory, we set out to fate map the output of the subpallial ganglionic eminences. Our initial approach utilized ultrasound backscatter microscopy to perform homotopic and heterotopic transplants of genetically marked progenitors from the lateral, medial and caudal ganglionic eminences (LGE, MGE and CGE, respectively) to unmarked host brains. The LGE, at least in the context of our transplant studies, did not appear to generate cortical interneurons. By contrast, we found that that approximately eighty percent of cortical interneurons arise from the MGE, while the remaining twenty percent were generated by the CGE. Hence, the majority of interneuron subtypes, including all fast spiking parvalbumin-positive basket cells and somatostatin-positive Martinotti cells appear to arise from the MGE. A more restricted set of cortical interneurons seems to be generated in the CGE, the majority of which are bipolar calretinin/VIP-positive interneurons. Complementing these results, we have recently demonstrated using inducible genetic fate mapping that the MGE produces specific cortical interneuron subtypes at discrete timepoints during development. These studies demonstrate that cortical interneurons arise from a precise developmental programme that acts in both space and time. Beyond this however, it seems likely that postmitotic events influence the specific function of subclasses of cortical interneurons. A primary challenge in the future will be to investigate what aspects of interneuron diversity are determined by intrinsic genetic programmes within each lineage versus those properties imposed by the local environment in the cortex.
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July 2008

Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip.

Neural Dev 2007 Feb 23;2. Epub 2007 Feb 23.

New York University School of Medicine, Smilow Neuroscience Program, Department of Cell Biology, 522 First Avenue, New York, NY 10016, USA.

Background: During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known.

Results: Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.

Conclusion: Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.
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http://dx.doi.org/10.1186/1749-8104-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1820780PMC
February 2007