PTF1-J is a trimeric transcription factor complex essential for generating the correct balance of GABAergic and glutamatergic interneurons in multiple regions of the nervous system, including the dorsal horn of the spinal cord and the cerebellum. Although the components of PTF1-J have been identified as the basic helix-loop-helix (bHLH) factor Ptf1a, its heterodimeric E-protein partner, and Rbpj, no neural targets are known for this transcription factor complex. Here we identify the neuronal differentiation gene Neurog2 (Ngn2, Math4A, neurogenin 2) as a direct target of PTF1-J. A Neurog2 dorsal neural tube enhancer localized 3' of the Neurog2 coding sequence was identified that requires a PTF1-J binding site for dorsal activity in mouse and chick neural tube. Gain and loss of Ptf1a function in vivo demonstrate its role in Neurog2 enhancer activity. Furthermore, chromatin immunoprecipitation from neural tube tissue demonstrates that Ptf1a is bound to the Neurog2 enhancer. Thus, Neurog2 expression is directly regulated by the PTF1-J complex, identifying Neurog2 as the first neural target of Ptf1a and revealing a bHLH transcription factor cascade functioning in the specification of GABAergic neurons in the dorsal spinal cord and cerebellum.
"Non-mammalian or non-neuronal studies were excluded by scrutinizing titles, abstracts and “Materials and Methods.” The hypothetical functional gene network contains the 13 candidates and a subset of the 28 genes that interacted with more than one gene found through the literature mining approach (Pani et al., 2002; Scardigli, 2003; Li et al., 2004, 2012a,b; Schuurmans et al., 2004; Yang et al., 2004; Taranova et al., 2006; Allen et al., 2007; Taylor et al., 2007; Nakazaki et al., 2008; Sawada et al., 2008; Shimizu et al., 2008; Shimojo et al., 2008; Wen et al., 2008; Yu et al., 2008; Favaro et al., 2009; Fernandez et al., 2009; Henke et al., 2009; Ochiai et al., 2009; Aguirre et al., 2010; Hu et al., 2010; Kaltezioti et al., 2010; Qu et al., 2010, 2013; Chavali et al., 2011; Gee et al., 2011; Karalay et al., 2011; Sinor-Anderson and Lillien, 2011; Taniguchi et al., 2012; Xia et al., 2012; Zhao et al., 2012, 2014; Zhang et al., 2012a,b, 2013; Imamura and Greer, 2013; Marqués-Torrejón et al., 2013; Petrova et al., 2013; Misra et al., 2014). Note that we listed only one article for each interaction (selection priority (original research articles only): in vivo > in vitro; direct interaction > indirect interaction). "
[Show abstract][Hide abstract] ABSTRACT: Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8-9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2 and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
Frontiers in Neuroscience 08/2014; 8(8). DOI:10.3389/fnins.2014.00257 · 3.66 Impact Factor
"This could be the case in the retina where, although the Ascl1 and Neurog2 lineages are largely distinct, such progenitors expressing both genes have recently been described . Interestingly, Neurog2 was identified as a direct transcriptional target of Ptf1a in the chick dorsal spinal cord and cerebellum , two regions where Ptf1a, Ascl1 and Neurog2 expressions partially overlap . Neurog2 might thus participate within these domains in the Ascl1/Ptf1a-dependent GABAergic program. "
[Show abstract][Hide abstract] ABSTRACT: In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis.
PLoS ONE 03/2014; 9(3):e92113. DOI:10.1371/journal.pone.0092113 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice.
PLoS ONE 02/2014; 9(2):e86471. DOI:10.1371/journal.pone.0086471 · 3.23 Impact Factor
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