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Regulation of Tlx3 by Pax6 is required for the restricted expression of ChrnÎ±3 in Cerebellar Granule Neuron progenitors during development

ABSTRACT: Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6-/-Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-Î±3 subunit (ChrnÎ±3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD) Anterior and posterior lobes of PN7 mouse cerebellum were isolated separately and differentially expressed genes were identified.

ORGANISM(S): Mus musculus

SUBMITTER: madavan vasudevan

PROVIDER: E-GEOD-82097 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of Tlx3 by Pax6 is required for the restricted expression of Chrnα3 in Cerebellar Granule Neuron progenitors during development

Project description:Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6-/-Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-α3 subunit (Chrnα3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD)

2016-06-30 | GSE82097 | GEO

A peptidomic approach to characterize peptides involved in cerebellar cortex development leads to the identification of the neurotrophic effects of nociceptin

Project description:The cerebellum is a brain structure involved in motor and cognitive functions. The development of the cerebellar cortex (the external part of the cerebellum) is under the control of numerous factors. Among these factors, neuropeptides including PACAP or somatostatin modulate the survival, migration and/or differentiation of cerebellar granule cells. Interestingly, such peptides contributing to cerebellar ontogenesis usually exhibit a specific transient expression profile with a low abundance at birth, a high expression level during the developmental processes, which take place within the first two postnatal weeks in rodents, and a gradual decline toward adulthood. Thus, to identify new peptides transiently expressed in the cerebellum during development, rat cerebella were sampled from birth to adulthood, and analyzed by a semi-quantitative peptidomic approach. A total of 33 peptides were found to be expressed in the cerebellum. Among these 33 peptides, 8 had a clear differential expression pattern during development, 4 of them i.e. cerebellin 2, nociceptin, somatostatin and VGF [353-372], exhibiting a high expression level during the first two postnatal weeks followed by a significative decrease at adulthood. A focus by a genomic approach on nociceptin, confirmed that the precursor mRNA is transiently expressed during the first week of life in granule neurons within the internal granule cell layer of the cerebellum, and showed that the nociceptin receptor is also actively expressed between P8 and P16 by the same neurons. Finally, functional studies revealed a new role for nociceptin, acting as a neurotrophic peptide able to promote the survival and differentiation of developing cerebellar granule neurons.

2018-06-15 | PXD006874 | Pride

Mus musculus

Project description:Regulation of Tlx3 by Pax6 is required for the restricted expression of Chrnα3 in Cerebellar Granule Neuron progenitors during development

| PRJNA324002 | ENA

The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

Project description:Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional knockout of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal mouse brain. In laser capture microdissection followed by RNASeq, designed to profile gene expression specifically in the external granule layer (EGL) of the cerebellum, we find that SnoN promotes the expression of cell proliferation genes and concomitantly represses differentiation genes in granule neuron precursors in vivo. Remarkably, bioinformatics analyses reveal that SnoN-regulated genes contain binding sites for the transcription factors N-myc and Pax6, which promote the proliferation and differentiation of granule neuron precursors, respectively. Accordingly, we uncover novel physical interactions of SnoN with N-myc and Pax6 in cells. In behavior analyses, conditional knockout of SnoN impairs cerebellar-dependent learning in a delayed eye-blink conditioning paradigm, suggesting that SnoN-regulation of granule neuron precursor proliferation bears functional consequences at the organismal level. Our findings define a novel function and mechanism for the major transcriptional regulator SnoN in the control of granule neuron precursor proliferation in the mammalian brain.

2018-12-10 | GSE120276 | GEO

The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

2018-12-10 | GSE120278 | GEO

Gene expression of cerebellar granule cell layer

Project description:We performed gene-expression analysis of mouse cerebellar granule cell layer as compared to that of Purkinje cells. DNA microarray analysis detected genes in cerebellar granule cell layer, most of which are classified into functional molecule categories. Our comparative analysis between Purkinje cells and the granule cell layer showed that the characteristic expression pattern in Purkinje cells was particularly represented by M-bM-^@M-^\the neural communication systemM-bM-^@M-^] components. Pukinje cells and granule cell layer of the mouse cerebellum were collected by laser microdissection for RNA extraction and hybridization on Affymetrix microarrays.

2013-01-17 | E-GEOD-26750 | biostudies-arrayexpress

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

Project description:Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals, and cell types make the cerebellum an excellent model for addressing the critical function of polarity complex proteins in the generation and organization of neural tissues. Deleting apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors (CGNP) in the external granule layer (EGL). In the Pals1 mutants, expression of genes that regulate cell cycle were diminished, correlating with the loss of proliferating population of germinal zones. Furthermore, enhanced Shh signaling through activated Smoothened (Smo) cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a new intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling. Two groups of samples are included: mRNA obtained from 4 WT and 4 CKO animals at E17.5. hGFAP-Cre mice was used to delete Pals1 from most cerebellar neurons and glia (termed Pals1 CKO). Pals1fl/fl and hGFAP-Cre (Zhuo et al., 2001) were bred for generation of CKO.

2016-06-30 | E-GEOD-75696 | biostudies-arrayexpress

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

2016-06-30 | GSE75696 | GEO

Combined single-cell and spatial transcriptomics reveal the precise cellular states of postnatal cerebellar granule cells and connection with medulloblastoma

Project description:The progenitor/differentiation states of cerebellum granule cells have been investigated for many years. Deregulation of granule cells development is associated with the pathogenesis of medulloblastoma (MB).Our study reveals the cellular and spatial organization of cerebellar granule cells and provide direct evidence showing the similarity and discrepancy between normal development and tumorigenesis.

2021-01-18 | GSE156633 | GEO

Epigenomic Activation of Enhancers in Granule Cell Precursors by CHARGE Syndrome Protein CHD7 Regulates Gyrification of the Mammalian Cerebellum

Project description:Regulation of chromatin plays fundamental roles in the normal development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that prominently affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes the accessibility and activity of enhancers in granule cell precursors. Remarkably, in vivo profiling of genome architecture reveals that CHD7 operates locally to stimulate enhancer activation, thereby driving the expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated prominently with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define CHD7 function in the regulation of the epigenome in granule cell precursors and identify a surprising link of CHD7 to the control of cerebellar cortical morphogenesis, with potential implications for our understanding of CHARGE syndrome.

2021-04-07 | GSE164360 | GEO

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