Publications by authors named "Andrea Faedo"

17 Publications

  • Page 1 of 1

Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease.

Stem Cell Reports 2020 05 16;14(5):876-891. Epub 2020 Apr 16.

Department of Biosciences, University of Milan, Milan, 20133 Italy; Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, 20122 Italy. Electronic address:

Huntington disease (HD) is an inherited late-onset neurological disorder characterized by progressive neuronal loss and disruption of cortical and basal ganglia circuits. Cell replacement using human embryonic stem cells may offer the opportunity to repair the damaged circuits and significantly ameliorate disease conditions. Here, we showed that in-vitro-differentiated human striatal progenitors undergo maturation and integrate into host circuits upon intra-striatal transplantation in a rat model of HD. By combining graft-specific immunohistochemistry, rabies virus-mediated synaptic tracing, and ex vivo electrophysiology, we showed that grafts can extend projections to the appropriate target structures, including the globus pallidus, the subthalamic nucleus, and the substantia nigra, and receive synaptic contact from both host and graft cells with 6.6 ± 1.6 inputs cell per transplanted neuron. We have also shown that transplants elicited a significant improvement in sensory-motor tasks up to 2 months post-transplant further supporting the therapeutic potential of this approach.
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http://dx.doi.org/10.1016/j.stemcr.2020.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220987PMC
May 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Dynamic and Cell-Specific DACH1 Expression in Human Neocortical and Striatal Development.

Cereb Cortex 2019 05;29(5):2115-2124

Department of Biosciences, Istituto Nazionale di Genetica Molecolare, University of Milan and INGM, Milan, Italy.

DACH1 is the human homolog of the Drosophila dachshund gene, which is involved in the development of the eye, nervous system, and limbs in the fly. Here, we systematically investigate DACH1 expression patterns during human neurodevelopment, from 5 to 21 postconceptional weeks. By immunodetection analysis, we found that DACH1 is highly expressed in the proliferating neuroprogenitors of the developing cortical ventricular and subventricular regions, while it is absent in the more differentiated cortical plate. Single-cell global transcriptional analysis revealed that DACH1 is specifically enriched in neuroepithelial and ventricular radial glia cells of the developing human neocortex. Moreover, we describe a previously unreported DACH1 expression in the human striatum, in particular in the striatal medium spiny neurons. This finding qualifies DACH1 as a new striatal projection neuron marker, together with PPP1R1B, BCL11B, and EBF1. We finally compared DACH1 expression profile in human and mouse forebrain, where we observed spatio-temporal similarities in its expression pattern thus providing a precise developmental description of DACH1 in the 2 mammalian species.
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http://dx.doi.org/10.1093/cercor/bhy092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458905PMC
May 2019

Differentiation of human telencephalic progenitor cells into MSNs by inducible expression of Gsx2 and Ebf1.

Proc Natl Acad Sci U S A 2017 02 30;114(7):E1234-E1242. Epub 2017 Jan 30.

Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy;

Medium spiny neurons (MSNs) are a key population in the basal ganglia network, and their degeneration causes a severe neurodegenerative disorder, Huntington's disease. Understanding how ventral neuroepithelial progenitors differentiate into MSNs is critical for regenerative medicine to develop specific differentiation protocols using human pluripotent stem cells. Studies performed in murine models have identified some transcriptional determinants, including GS Homeobox 2 (Gsx2) and Early B-cell factor 1 (Ebf1). Here, we have generated human embryonic stem (hES) cell lines inducible for these transcription factors, with the aims of () studying their biological role in human neural progenitors and () incorporating TF conditional expression in a developmental-based protocol for generating MSNs from hES cells. Using this approach, we found that Gsx2 delays cell-cycle exit and reduces Pax6 expression, whereas Ebf1 promotes neuronal differentiation. Moreover, we found that Gsx2 and Ebf1 combined overexpression in hES cells achieves high yields of MSNs, expressing Darpp32 and Ctip2, in vitro as well in vivo after transplantation. We show that hES-derived striatal progenitors can be transplanted in animal models and can differentiate and integrate into the host, extending fibers over a long distance.
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http://dx.doi.org/10.1073/pnas.1611473114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321017PMC
February 2017

Genome-Wide Definition of Promoter and Enhancer Usage during Neural Induction of Human Embryonic Stem Cells.

PLoS One 2015 15;10(5):e0126590. Epub 2015 May 15.

Genethon, Evry, France; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Genome-wide mapping of transcriptional regulatory elements is an essential tool for understanding the molecular events orchestrating self-renewal, commitment and differentiation of stem cells. We combined high-throughput identification of transcription start sites with genome-wide profiling of histones modifications to map active promoters and enhancers in embryonic stem cells (ESCs) induced to neuroepithelial-like stem cells (NESCs). Our analysis showed that most promoters are active in both cell types while approximately half of the enhancers are cell-specific and account for most of the epigenetic changes occurring during neural induction, and most likely for the modulation of the promoters to generate cell-specific gene expression programs. Interestingly, the majority of the promoters activated or up-regulated during neural induction have a "bivalent" histone modification signature in ESCs, suggesting that developmentally-regulated promoters are already poised for transcription in ESCs, which are apparently pre-committed to neuroectodermal differentiation. Overall, our study provides a collection of differentially used enhancers, promoters, transcription starts sites, protein-coding and non-coding RNAs in human ESCs and ESC-derived NESCs, and a broad, genome-wide description of promoter and enhancer usage and of gene expression programs characterizing the transition from a pluripotent to a neural-restricted cell fate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126590PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433211PMC
April 2016

Human pluripotent stem cell differentiation into authentic striatal projection neurons.

Stem Cell Rev Rep 2013 Aug;9(4):461-74

Department of Biosciences and Center for Stem Cell Research, Università degli Studi di Milano, 20133 Milan, Italy.

Here we present the principles and steps of a protocol that we have recently developed for the differentiation of hES/iPS cells into the authentic human striatal projection medium spiny neurons (MSNs) that die in Huntington's Disease (HD). Authenticity is judged by the convergence of multiple features within individual cells. Our procedure lasts 80 days and couples neural induction via BMP/TGF-β inhibition with exposure to the developmental factors sonic hedgehog (SHH) and dickkopf1 (DKK-1) to drive ventral telencephalic specification, followed by terminal differentiation [1]. Authenticity of the resulting neuronal population is monitored by the appearance of FOXG1(+)/GSX2(+) progenitor cells of the lateral ganglionic eminence (LGE) at day 15-25 of differentiation, followed by appearance of CTIP2-, FOXP1- and FOXP2-positive cells at day 45. These precursor cells then mature into MAP2(+)/GABA(+) neurons with 20 % of them ultimately co-expressing the DARPP-32 and CTIP2 diagnostic markers and carrying electrophysiological properties expected for fully functional MSNs.The protocol is characterized by its replicability in at least three human pluripotent cell lines. Altogether this protocol defines a useful platform for in vitro developmental neurobiology studies, drug screening, and regenerative medicine approaches.
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http://dx.doi.org/10.1007/s12015-013-9441-8DOI Listing
August 2013

CoupTFI interacts with retinoic acid signaling during cortical development.

PLoS One 2013 5;8(3):e58219. Epub 2013 Mar 5.

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

We examined the role of the orphan nuclear hormone receptor CoupTFI in mediating cortical development downstream of meningeal retinoic acid signaling. CoupTFI is a regulator of cortical development known to collaborate with retinoic acid (RA) signaling in other systems. To examine the interaction of CoupTFI and cortical RA signaling we utilized Foxc1-mutant mice in which defects in meningeal development lead to alterations in cortical development due to a reduction of RA signaling. By analyzing CoupTFI(-/-);Foxc1(H/L) double mutant mice we provide evidence that CoupTFI is required for RA rescue of the ventricular zone and the neurogenic phenotypes in Foxc1-mutants. We also found that overexpression of CoupTFI in Foxc1-mutants is sufficient to rescue the Foxc1-mutant cortical phenotype in part. These results suggest that CoupTFI collaborates with RA signaling to regulate both cortical ventricular zone progenitor cell behavior and cortical neurogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058219PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589372PMC
December 2013

Sp8 and COUP-TF1 reciprocally regulate patterning and Fgf signaling in cortical progenitors.

Cereb Cortex 2014 Jun 10;24(6):1409-21. Epub 2013 Jan 10.

Inserm U846, Stem Cell and Brain Research Institute, Bron 69500, France.

To gain new insights into the transcriptional regulation of cortical development, we examined the role of the transcription factor Sp8, which is downstream of Fgf8 signaling and known to promote rostral cortical development. We have used a binary transgenic system to express Sp8 throughout the mouse telencephalon in a temporally restricted manner. Our results show that misexpression of Sp8 throughout the telencephalon, at early but not late embryonic stages, results in cortical hypoplasia, which is accompanied by increased cell death, reduced proliferation, and precocious neuronal differentiation. Misexpression of Sp8 at early developmental stages represses COUP-TF1 expression, a negative effector of Fgf signaling and a key promoter of posterior cortical identity, while ablation of Sp8 has the opposite effect. In addition, transgenic misexpression of COUP-TF1 resulted in downregulation of Sp8, indicating a reciprocal cross-regulation between these 2 transcription factors. Although Sp8 has been suggested to induce and/or maintain Fgf8 expression in the embryonic telencephalon, neither Fgf8 nor Fgf15 was upregulated using our gain-of-function approach. However, misexpression of Sp8 greatly increased the expression of Fgf target molecules, suggesting enhanced Fgf signaling. Thus, we propose that Sp8 promotes rostral and dorsomedial cortical development by repressing COUP-TF1 and promoting Fgf signaling in pallial progenitors.
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http://dx.doi.org/10.1093/cercor/bhs412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014177PMC
June 2014

Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons.

Development 2013 Jan;140(2):301-12

Center for Stem Cell Research, Università degli Studi di Milano, 20133 Milan, Italy.

Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons, and their degeneration underlies some of the clinical features of Huntington's disease. Using knowledge of human developmental biology and exposure to key neurodevelopmental molecules, human pluripotent stem (hPS) cells were induced to differentiate into MSNs. In a feeder-free adherent culture, ventral telencephalic specification is induced by BMP/TGFβ inhibition and subsequent SHH/DKK1 treatment. The emerging FOXG1(+)/GSX2(+) telencephalic progenitors are then terminally differentiated, resulting in the systematic line-independent generation of FOXP1(+)/FOXP2(+)/CTIP2(+)/calbindin(+)/DARPP-32(+) MSNs. Similar to mature MSNs, these neurons carry dopamine and A2a receptors, elicit a typical firing pattern and show inhibitory postsynaptic currents, as well as dopamine neuromodulation and synaptic integration ability in vivo. When transplanted into the striatum of quinolinic acid-lesioned rats, hPS-derived neurons survive and differentiate into DARPP-32(+) neurons, leading to a restoration of apomorphine-induced rotation behavior. In summary, hPS cells can be efficiently driven to acquire a functional striatal fate using an ontogeny-recapitulating stepwise method that represents a platform for in vitro human developmental neurobiology studies and drug screening approaches.
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http://dx.doi.org/10.1242/dev.084608DOI Listing
January 2013

Repression of Fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times.

J Neurosci 2010 Mar;30(11):4015-23

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158-2611, USA.

A fundamental question in developmental biology is how signaling pathways establish a transcription factor code that controls cell proliferation, regional fate and cell fate. Morphogenesis of the rostral telencephalon is controlled in part by Fgf signaling from the rostral patterning center. How Fgf signaling is regulated in the telencephalon is critical for understanding cerebral cortex formation. Here we show that mouse Sprouty1 and Sprouty2 (Spry1-2), which encode negative feedback regulators of Fgf signaling, are affecting cortical proliferation, differentiation, and the expression of genes regulating progenitor identity in the ventricular zone. In addition, Spry2 has a later function in regulating the MAPK pathway, proliferation, and gene expression in the cortex at mid-neurogenesis. Finally, we provide evidence that Coup-TFI, a transcription factor that promotes caudal fate, does so through repressing Fgf signaling, in part by promoting Spry expression.
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http://dx.doi.org/10.1523/JNEUROSCI.0307-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852648PMC
March 2010

The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

PLoS Genet 2009 Jun 12;5(6):e1000511. Epub 2009 Jun 12.

Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.

Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal.
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http://dx.doi.org/10.1371/journal.pgen.1000511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686252PMC
June 2009

COUP-TFI coordinates cortical patterning, neurogenesis, and laminar fate and modulates MAPK/ERK, AKT, and beta-catenin signaling.

Cereb Cortex 2008 Sep 28;18(9):2117-31. Epub 2007 Dec 28.

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA 94158, USA.

A major unsolved question in cortical development is how proliferation, neurogenesis, regional growth, regional identity, and laminar fate specification are coordinated. Here we provide evidence, using loss-of-function and gain-of-function manipulations, that the COUP-TFI orphan nuclear receptor promotes ventral cortical fate, promotes cell cycle exit and neural differentiation, regulates the balance of early- and late-born neurons, and regulates the balanced production of different types of layer V cortical projection neurons. We suggest that COUP-TFI controls these processes by repressing Mapk/Erk, Akt, and beta-catenin signaling.
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http://dx.doi.org/10.1093/cercor/bhm238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733307PMC
September 2008

Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism.

Dev Biol 2007 Feb 22;302(1):50-65. Epub 2006 Aug 22.

Genes and Development Group, Department of Biomedical Sciences, Centres for Integrative Physiology and Neuroscience Research, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.

Many cerebral cortical neurons and glia are produced by apical progenitors dividing at the ventricular surface of the embryonic dorsal telencephalon. Other neurons are produced by basal progenitor cells, which are derived from apical progenitors, dividing away from the ventricular surface. The transcription factor Pax6 is expressed in apical progenitors and is downregulated in basal progenitors, which upregulate the transcription factor Tbr2. Here we show that Pax6(-/-) cells are under-represented in the cortex of Pax6(+/+)<-->Pax6(-/-) chimeras early in corticogenesis, indicating that Pax6 is required for the production of normal numbers of cortical cells. We provide evidence that this underproduction is attributable to an early depletion of the progenitor pool caused by greater than normal proportions of newly divided cells exiting the cell cycle. We show that most progenitor cells dividing away from the ventricular surface in Pax6(-/-) embryos fail to express the transcription factor Tbr2 and that Pax6 is required cell autonomously for Tbr2 expression in the developing cortex of Pax6(+/+)<-->Pax6(-/-) chimeras. Transcription factors normally expressed ventrally in the telencephalic ganglionic eminences (Mash1, Dlx2 and Gsh2) are upregulated cell autonomously in mutant cells in the developing cortex of Pax6(+/+)<-->Pax6(-/-) chimeras; Nkx2.1, which is expressed only in the medial ganglionic eminence, is not. These data indicate that early functions of Pax6 in developing cortical cells are to repress expression of transcription factors normally found in the lateral ganglionic eminence, to prevent precocious differentiation and depletion of the progenitor pool, and to induce normal development of cortical basal progenitor cells.
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http://dx.doi.org/10.1016/j.ydbio.2006.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2384163PMC
February 2007

Telencephalic embryonic subtractive sequences: a unique collection of neurodevelopmental genes.

J Neurosci 2005 Aug;25(33):7586-600

Stem Cell Research Institute-Hospital San Raffaele, Istituto Scientifico San Raffaele, 20132 Milan, Italy.

The vertebrate telencephalon is composed of many architectonically and functionally distinct areas and structures, with billions of neurons that are precisely connected. This complexity is fine-tuned during development by numerous genes. To identify genes involved in the regulation of telencephalic development, a specific subset of differentially expressed genes was characterized. Here, we describe a set of cDNAs encoded by genes preferentially expressed during development of the mouse telencephalon that was identified through a functional genomics approach. Of 832 distinct transcripts found, 223 (27%) are known genes. Of the remaining, 228 (27%) correspond to expressed sequence tags of unknown function, 58 (7%) are homologs or orthologs of known genes, and 323 (39%) correspond to novel rare transcripts, including 48 (14%) new putative noncoding RNAs. As an example of this latter group of novel precursor transcripts of micro-RNAs, telencephalic embryonic subtractive sequence (TESS) 24.E3 was functionally characterized, and one of its targets was identified: the zinc finger transcription factor ZFP9. The TESS transcriptome has been annotated, mapped for chromosome loci, and arrayed for its gene expression profiles during neural development and differentiation (in Neuro2a and neural stem cells). Within this collection, 188 genes were also characterized on embryonic and postnatal tissue by in situ hybridization, demonstrating that most are specifically expressed in the embryonic CNS. The full information has been organized into a searchable database linked to other genomic resources, allowing easy access to those who are interested in the dissection of the molecular basis of telencephalic development.
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http://dx.doi.org/10.1523/JNEUROSCI.0522-05.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725394PMC
August 2005

Identification and characterization of a novel transcript down-regulated in Dlx1/Dlx2 and up-regulated in Pax6 mutant telencephalon.

Dev Dyn 2004 Nov;231(3):614-20

Stem Cell Research Institute, Dibit, H.S. Raffaele, Via Olgettina 58, 20132 Milan, Italy.

By using a custom-made array containing cDNAs preferentially expressed in the mouse embryonic telencephalon (Porteus et al. [1992] Brain Res Mol Brain Res 12:7-22; and Alessandro Bulfone, unpublished data), we studied the gene expression profile of the Dlx1/Dlx2(-/-) subpallium and Pax6(-/-) pallium. We identified a transcript corresponding to Unigene Cluster Mm.94021 and rat Evf-1, which is down-regulated in the Dlx1/Dlx2(-/-) subpallium and up-regulated in the Pax6(-/-) pallium. Here, we report the expression pattern of this transcript, designated mouse Evf1 (mEvf1), in the prenatal forebrain of wild-type, Dlx1/Dlx2(-/-) and Pax6(-/-) mice using RNA in situ hybridization and reverse transcriptase-polymerase chain reaction. In the wild-type forebrain mEvf1 expression is restricted to the ventral thalamus, hypothalamus, and subpallial telencephalon (caudal, lateral, and medial ganglionic eminences and septal primordia), whereas it is down-regulated in the Dlx1/Dlx2(-/-) subpallium (mainly in caudal, lateral, and medial ganglionic eminences), and up-regulated in the Pax6(-/-) lateral and ventral pallium at embryonic day 12.5 and in the dorsal, lateral, and ventral pallium at embryonic day 14.5.
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http://dx.doi.org/10.1002/dvdy.20152DOI Listing
November 2004

Pcp4l1, a novel gene encoding a Pcp4-like polypeptide, is expressed in specific domains of the developing brain.

Gene Expr Patterns 2004 May;4(3):297-301

Stem Cell Research Institute (SCRI), Istituto Scientifico San Raffaele (HSR), Via Olgettina 58, Milan 20132, Italy.

We report the cloning of a novel mouse gene (Pcp4l1) that encodes a polypeptide with significant sequence similarity to the Purkinje cell protein 4 gene (Pcp4) and describe its expression pattern during mouse development. Similar to Pcp4, the Pc4l1 gene product is characterized by the presence of an IQ domain and is highly conserved across evolution. RNA in situ hybridization reveals instead that Pcp4l1 has a distinct pattern of expression: it is only expressed in the central nervous system (CNS), and is first detected at E9.5 in the mesencephalic and metencephalic roof plate as well as in the isthmus, in a region that overlaps the expression domains of Pax2, Fgf8 and Wnt1. Thus, the early Pcp4l1 expression pattern coincides with the regional expression of well-characterized patterning molecules in the organizing centers of the developing brain. Starting at midgestation, Pcp4l1 is mainly expressed in the structures of the circumventricular organs, including the subcommissural organ, the rhombencephalic and telencephalic choroid plexi, and the pineal gland. In the adult brain, this transcript is also detected in laminar as well as in several nuclear structures of the CNS.
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http://dx.doi.org/10.1016/j.modgep.2003.11.001DOI Listing
May 2004

Developmental expression of the T-box transcription factor T-bet/Tbx21 during mouse embryogenesis.

Mech Dev 2002 Aug;116(1-2):157-60

Stem Cell Research Institute (SCRI), Istituto Scientifico HS Raffaele, Via Olgettina, 58 Milan, Italy.

A novel type of DNA-binding domain, the 'T-box' domain, characterizes an increasingly large family of transcription factors (Trends Genet. 15 (1999) 154). We have identified and characterized the expression pattern of a new member of the Tbr1 subfamily of T-box genes; this gene has been recently named T-bet/Tbx21 (Genomics 70 (2000) 41; Cell 17 (2000) 655; Science 292 (2001) 1907; Science 295 (2002) 338). The sequence and expression of Tbr1 and eomesodermin/Tbr2 are closely related to T-bet/Tbx21. The expression of Tbr1 (Neuron 15 (1995) 63) and Tbr2 (Mech Dev 84 (1999) 133) have virtually identical onset, at around E10.5, and expression domains in the mouse telencephalon. While Tbr1 is expressed in postmitotic neurons, Tbr2 (which is also expressed during gastrulation is also expressed in neural progenitors. We have used in situ hybridization to determine the temporal and spatial distribution of T-bet/Tbx21 expression during mouse development. T-bet/Tbx21 expression is exclusively restricted to the olfactory bulb and the thymus. To assess the distribution of T-BET/TBX21 expression in the haematopoietic compartment we used reverse transcriptase-polymerase chain reaction and found its expression in several human blood cell lineages, including progenitors/stem cells, immature B cells and peripheral T cells.
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http://dx.doi.org/10.1016/s0925-4773(02)00114-4DOI Listing
August 2002