Neuronal Expression of Regulatory Helix-Loop-Helix Factor Id2 Gene in Mouse

doi:10.1006/dbio.1993.1297

Developmental Biology

Volume 160, Issue 1, November 1993, Pages 186-195

https://doi.org/10.1006/dbio.1993.1297 Get rights and content

Abstract

Id-like helix-loop-helix (HLH) proteins, which lack a basic DNA binding domain, have been suggested to serve as general inhibitors of differentiation. We present data that Id2 is expressed in specific cell types during neurogenesis and in the adult. At early stages of neurogenesis, Id2 is expressed in the ventricular zone of neuroepithelium. After the first neuronal populations are born, the expression of Id2 is down regulated in neuroepithelial cells and continues to be high in Purkinje cells of the cerebellum, in mitral cells of the olfactory bulb, and in layers 2, 3, and 5 of the cerebral cortex. In neuronally differentiating cell lines, the Id2 expression is up regulated (PCC7), down regulated (NG108), or unchanged (N18) during differentiation. Analyses of promoter sequences of the Id2 gene identify the region which is responsible for the down regulation of transcription during neuronal differentiation. Our data indicate that Id2 has different functions in different cell types during neurogenesis.

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The mammalian neocortex is most evolutionarily advanced region of the brain, responsible for sensory perception, integrative-associative function, voluntary motor control, and high-level cognition; it has undergone dramatic expansion during evolution. This capacity for high-order processing emerges from a complex, yet highly organized, six-layered sheet-like structure divided into functionally and cytoarchitectonically distinct areas that contain many distinct neuronal subtypes with function-specific molecular, connectivity and physiological properties. Here, the development and organization of the neocortex are reviewed in the context of recent results revealing functions of individual and combinatorial sets of genes in controlling specification, development, connectivity, and areal function-specific diversity of distinct projection neuron subtypes. First, we describe the diversity of progenitors that give rise to the projection neurons of the neocortex, and discuss current knowledge regarding molecular-genetic programs that regulate progenitor specification, lineage potential, and plasticity. Next, we focus on two distinct, broad projection neuron classes, corticofugal (cortical output) projection neurons and callosal projection neurons (the dominant inter-hemispheric neurons in placental mammals). We describe recent advances in understanding the interplay of combinatorial and sequential molecular-genetic controls over the precise generation and diversity of these developmentally and clinically important neuronal subtypes. Then, we review some possibilities for applying the expanding knowledge of developmental biology of neocortical subtype-specific differentiation toward directed differentiation of human pluripotent stem cells and cellular repair strategies. Finally, we briefly discuss an emerging field regarding implementation of circuit-specific axonal connectivity, circuit formation, and function by subtype-specific subcellular domains, in particular growth cones.
Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis
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Citation Excerpt :
They are involved in multiple physiological and pathological processes, acting on cell growth, differentiation, senescence and survival (Lasorella et al., 2014; Ling et al., 2014; Sikder et al., 2003; Yokota, 2001). The different Id genes play key roles in embryonic and adult neurogenesis by regulating quiescence and self-renewal of neural stem cells as well as neuronal differentiation (Aloia et al., 2015; Bai et al., 2007; Havrda et al., 2008; Jen et al., 1997; Jung et al., 2010; Lyden et al., 1999; Nam and Benezra, 2009; Neuman et al., 1993; Ohtaka-Maruyama et al., 2007). Given that expression patterns of Id proteins strongly overlap in various tissues, redundancy in their function has been suggested (Langlands et al., 1997; Sun et al., 1991).
Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish.
Transcription factors expressed in olfactory bulb local progenitor cells revealed by genome-wide transcriptome profiling
2011, Molecular and Cellular Neuroscience
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For example, Mafb and Stmn2 (cluster 2) are expressed in a peripheral cell layer in the OB in both E15 and E18 embryos (Fig. 4D and E). This pattern most likely corresponds expression in the mitral cell layer since Id2 is expressed here at this developmental stage (Neuman et al., 1993) (Fig. 4F). Three other genes from cluster 3, Nr2f1, Foxo1, and Heyl, are expressed in the olfactory nerve layer (Fig. 4G–I).
The local progenitor population in the olfactory bulb (OB) gives rise to mitral and tufted projection neurons during embryonic development. In contrast, OB interneurons are derived from sources outside the bulb where neurogenesis continues throughout life. While many of the genes involved in OB interneuron development have been characterized, the genetic pathways driving local progenitor cell differentiation in this tissue are largely unknown. To better understand this process, we used transcriptional profiling to monitor gene expression of whole OB at daily intervals from embryonic day 11 through birth, generating a compendium of gene expression encompassing the major developmental events of this tissue. Through hierarchical clustering, bioinformatics analysis, and validation by RNA in situ hybridizations, we identified a large number of transcription factors, DNA binding proteins, and cell cycle-related genes expressed by the local neural progenitor cells (NPCs) of the embryonic OB. Further in silico analysis of transcription factor binding sites identified an enrichment of genes regulated by the E2F-Rb pathway among those expressed in the local NPC population. Together these results provide initial insights into the molecular identity of the OB local NPC population and the transcription factor networks that may regulate their function.
The inhibitor of DNA binding 2 is mainly expressed in oligodendrocyte lineage cells in adult rat brain
2007, Neuroscience Letters
The inhibitor of DNA binding 2 (Id2) plays an important role in the brain both during embryogenesis and adulthood. But in adult rat brain, it is still unknown whether Id2 immunoreactivity mainly exhibits in neuronal, astrocytic and/or oligodendrocyte lineage cells. It is also unclear where and when Id2 immunoreactivity mainly exhibits in oligodendrocyte lineage cells. The present study showed 90% of Id2-immunoreactivity in oligdendrocyte lineage cells in such brain regions as the corpus callosum, optic chiasm, the longitudinal fasciculus of pons, the medial septal nucleus, the fimbria of hippocampus, the anterior commissure, and the pyramidal tract. Five percent of Id2-immunoreactivity was found in astrocytes. Id2 immunoreactivity was localized in neurons of only a few brain regions. Seventy percent of Id2 immunoreactivity was found in CC-1-positive mature oligodendrocytes. These observations suggest that Id2 may be mainly involved in terminal maturation of oligodendrocytes and myelination.
shRNA Knockdown of Bmi-1 Reveals a Critical Role for p21-Rb Pathway in NSC Self-Renewal during Development
2007, Cell Stem Cell
Citation Excerpt :
Early stage forebrain progenitor cells are stimulated to divide and generate neurons by β-catenin signaling (Chenn and Walsh, 2002; Hirabayashi et al., 2004; Zechner et al., 2003; Shen et al., 2004). Id2 is normally expressed in ventricular zone cells at high levels, where it can inhibit bHLH differentiation pathways (Neuman et al., 1993), and Id2 can directly bind to Rb and inactivate it (Lasorella et al., 2005). These observations raise the hypothesis that Bmi-1-dependent regulation of p21-Rb pathway components alters NSC self-renewal properties at different stages of development.
Knockout studies have shown that the polycomb gene Bmi-1 is important for postnatal, but not embryonic, neural stem cell (NSC) self-renewal and have identified the cell-cycle inhibitors p16/p19 as molecular targets. Here, using lentiviral-delivered shRNAs in vitro and in vivo, we determined that Bmi-1 is also important for NSC self-renewal in the embryo. We found that neural progenitors depend increasingly on Bmi-1 for proliferation as development proceeds from embryonic through adult stages. Acute shRNA-mediated Bmi-1 reduction causes defects in embryonic and adult NSC proliferation and self-renewal that, unexpectedly, are mediated by a different cell-cycle inhibitor, p21. Gene array analyses revealed developmental differences in Bmi-1-controlled expression of genes in the p21-Rb cell cycle regulatory pathway. Our data therefore implicate p21 as an important Bmi-1 target in NSCs, potentially with stage-related differences. Understanding stage-related mechanisms underlying NSC self-renewal has important implications for development of stem cell-based therapies.
Localization of Id2 mRNA in the adult mouse brain
2006, Brain Research
Id proteins are negative regulators of basic helix–loop–helix transcription factors and are involved in cellular differentiation and proliferation. Four members of the Id gene family exhibit closely related but distinct expression patterns in various mammalian organs of not only embryos but also adults. Among them, Id2 is known to be expressed in Purkinje cells and neurons in the cortical layers of the adult mouse brain, suggesting that Id2 is involved in some neural functions in the adult. To get insight into the role of Id2 in the nervous system, we investigated the localization of Id2 mRNA-expressing cells in the adult mouse brain in detail by in situ hybridization with the radiolabeled antisense probe and compared it with the localization of other Id gene family members. The results indicated that Id2 mRNA is detected in more varied brain regions than previously reported. These regions include the amygdaloid complex, caudate putamen, globus pallidus, substantia nigra pars reticulata, suprachiasmatic nucleus, and the anterior part of the subventricular zone. These results suggest the possibility that Id2 plays a role in the neural activity and cognitive functions. On the other hand, Id1 was barely detectable. Although moderate or low expression of Id3 was observed diffusely, high expression was observed in some specific regions including the molecular layer of the dentate gyrus and the external capsule. Id4 mRNA was detected in the regions such as the caudate putamen and the lateral amygdaloid nucleus. Thus, the expression pattern of Id2 is distinct from those of other Id gene family members.

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Neuronal Expression of Regulatory Helix-Loop-Helix Factor Id2 Gene in Mouse