<i>Zic1</i>and<i>Zic3</i>Regulate Medial Forebrain Development through Expansion of Neuronal Progenitors

Inoue, Takashi; Ota, Maya; Ogawa, Miyuki; Mikoshiba, Katsuhiko; Aruga, Jun

doi:10.1523/jneurosci.4046-06.2007

Cited by 93 publications

(103 citation statements)

References 73 publications

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“…Interestingly, we uncovered a compensatory mechanism between the 2 genes that may ensure sufficient Zic activity when one member is inactivated, further highlighting their essential role. Functional redundancy has also been observed between zic genes in mutant mice, including in the zic1/zic3 double-knockout animals (21). Future work should address whether the role of Zic factors in neural induction is evolutionary conserved.…”

Section: Discussionmentioning

confidence: 96%

BMP inhibition initiates neural induction via FGF signaling and Zic genes

Marchal

Luxardi

Thomé

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

112

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Neural induction is the process that initiates nervous system development in vertebrates. Two distinct models have been put forward to describe this phenomenon in molecular terms. The default model states that ectoderm cells are fated to become neural in absence of instruction, and do so when bone morphogenetic protein (BMP) signals are abolished. A more recent view implicates a conserved role for FGF signaling that collaborates with BMP inhibition to allow neural fate specification. Using the Xenopus embryo, we obtained evidence that may unite the 2 views. We show that a dominant-negative R-Smad, Smad5-somitabun-unlike the other BMP inhibitors used previously-can trigger conversion of Xenopus epidermis into neural tissue in vivo. However, it does so only if FGF activity is uncompromised. We report that this activity may be encoded by FGF4, as its expression is activated upon BMP inhibition, and its knockdown suppresses endogenous, as well as ectopic, neural induction by Smad5-somitabun. Supporting the importance of FGF instructive activity, we report the isolation of 2 immediate early neural targets, zic3 and foxD5a. Conversely, we found that zic1 can be activated by BMP inhibition in the absence of translation. Finally, Zic1 and Zic3 are required together for definitive neural fate acquisition, both in ectopic and endogenous situations. We propose to merge the previous models into a unique one whereby neural induction is controlled by BMP inhibition, which activates directly, and, via FGF instructive activity, early neural regulators such as Zic genes. xenopus ͉ default model ͉ Smad5-sbn N eural induction is viewed as a decision made by gastrula ectodermal cells between neural and epidermal fates (1, 2). This process has been best studied in the Xenopus and chick embryos, which led to the emergence of distinct molecular models. The default model, based initially on Xenopus studies, has proposed that bone morphogenetic protein (BMP) inhibition is necessary and sufficient for neural induction (1). Studies in the chick have implicated additional instructive signals, among which FGF is an early and essential one (3, 4). However, one shared conclusion is that neural fate assignment requires the down-regulation of BMP signals (5, 6). What remains controversial is whether BMP inhibition could be sufficient for neural induction. Recently, we and others have introduced a paradigm to test the validity of the default model in frogs, which consists of micro-injection of cell-autonomously acting BMP inhibitors in ventral ectodermal cells of the 16-or 32-cell embryo (5, 6). Fate mapping combined to marker gene analysis indicate that these blastomeres normally give rise exclusively to epidermal cells (5). Those cells are competent for neuralization, but do not become neural if injected with Smad6 or a dominant-negative BMP receptor (5, 6). However, the epidermal-to-neural switch occurs when a low amount of FGF4 (called eFGF in the frog) is combined with those BMP inhibitors, supporting a combinatorial model (5, 6).It remaine...

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Section: Discussionmentioning

confidence: 96%

BMP inhibition initiates neural induction via FGF signaling and Zic genes

Marchal

Luxardi

Thomé

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

112

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“…Zic1 and Zic4 have been associated with Dandy-Walker syndrome and cerebellum development (Merzdorf, 2007;Inoue et al, 2007;Grinberg et al, 2004). In retinoic-acid-treated embryoid bodies, Zic1 silencing diminished neuronal differentiation without loss of Brn2 expression.…”

Section: Brn2 Is Upstream Of a Neurogenic Transcriptional Network In mentioning

confidence: 99%

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Urban

Kobi

Ennen

et al. 2015

Journal of Cell Science

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Mouse embryonic stem cells (ESCs) treated with all-trans retinoic acid differentiate into a homogenous population of glutamatergic neurons. Although differentiation is initiated through activation of target genes by the retinoic acid receptors, the downstream transcription factors specifying neuronal fate are less well characterised. Here, we show that the transcription factor Brn2 (also known as Pou3f2) is essential for the neuronal differentiation programme. By integrating results from RNA-seq following Brn2 silencing with results from Brn2 ChIP-seq, we identify a set of Brn2 target genes required for the neurogenic programme. Further integration of Brn2 ChIP-seq data from retinoicacid-treated ESCs and P19 cells with data from ESCs differentiated into neuronal precursors by Fgf2 treatment and that from fibroblasts trans-differentiated into neurons by ectopic Brn2 expression showed that Brn2 occupied a distinct but overlapping set of genomic loci in these differing conditions. However, a set of common binding sites and target genes defined the core of the Brn2-regulated neuronal programme, among which was that encoding the transcription factor Zic1. Small hairpin RNA (shRNA)-mediated silencing of Zic1 prevented ESCs from differentiating into neuronal precursors, thus defining a hierarchical Brn2-Zic1 axis that is essential to specify neural fate in retinoic-acid-treated ESCs.

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“…6G; Fig. 7A,B) (Pourebrahim et al, 2007;Brill et al, 2010;Watabe et al, 2011) and Zic3 (Inoue et al, 2007), or regulating the progression through the cell cycle, such as Id4 (Fig. 6G) (Yun et al, 2004).…”

Section: Leca4mentioning

confidence: 99%

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

et al. 2013

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To achieve adequate organ development and size, cell proliferation and differentiation have to be tightly regulated and coordinated. The transcription factor Pax6 regulates patterning, neurogenesis and proliferation in forebrain development. The molecular basis of this regulation is not well understood. As the bipartite DNA-binding paired domain of Pax6 regulates forebrain development, we examined mice with point mutations in its individual DNA-binding subdomains PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C). This revealed distinct roles in regulating proliferation in the developing cerebral cortex, with the PAI and RED subdomain mutations reducing and increasing, respectively, the number of mitoses. Conversely, neurogenesis was affected only by the PAI subdomain mutation, phenocopying the neurogenic defects observed in full Pax6 mutants. Genome-wide expression profiling identified molecularly discrete signatures of Pax6Leca4 and Pax6Leca2 mutations. Comparison to Pax6 targets identified by chromatin immunoprecipitation led to the identification and functional characterization of distinct DNA motifs in the promoters of target genes dysregulated in the Pax6Leca2 or Pax6Leca4 mutants, further supporting the distinct regulatory functions of the DNA-binding subdomains. Thus, Pax6 achieves its key roles in the developing forebrain by utilizing particular subdomains to coordinate patterning, neurogenesis and proliferation simultaneously.

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Zic1andZic3Regulate Medial Forebrain Development through Expansion of Neuronal Progenitors

Cited by 93 publications

References 73 publications

BMP inhibition initiates neural induction via FGF signaling and Zic genes

BMP inhibition initiates neural induction via FGF signaling and Zic genes

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

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