Lee HK , Lee HS , Moody SA .

NS23158 NINDS NIH HHS

Fig. 1. A schematic representation of main signaling pathways involved in NTFs development during embryogenesis. Five major signaling pathways including SHH, BMP, WNT, Notch ligands and FGF2, together crosstalk is represented. SHH ligand relieves the constitutive repression of the seven-pass receptor smoothened (SMO) by the modulation of the GLI transcriptional activators Gli1/2. Extracellular regulation of BMP signaling BMP induces the dimerization and then tetramerization of BMP receptors, leading to phosphorylation of the cytoplasmic signal transducer SMAD. WNT signaling activates β-catenin by modulating Frizzed and Dsh. Transcription factor LEF is required for enhancing of E2F1, consequently block Bmi1. The Notch and FGF2 signaling pathways have been implicated in regulating the neural differentiation and development. Notch interacts with NICD and mediates the effect of Hes1 and Gli/12. FGF2 activates JNK through binding with FGFR receptors, thus activating ATF2 regulatory mechanisms in neural development.

Fig. 2. A gene regulatory network of neural transcription factors that regulate the earliest steps in vertebrate neural development. Foxd4 is required for the expression of the remaining genes, and it directly activates Geminin, Zic2 and Sox11 (blue arrows). Together, these three genes mediate the downstream effects of Foxd4, which is to delay the expression of neural plate stem cell genes (Sox) and repress the expression of neural progenitor genes (Irx, Zic, bHLH).

Ahmed, Transcription factors and neural stem cell self-renewal, growth and differentiation. 2009, Pubmed

Ahmed, Transcription factors and neural stem cell self-renewal, growth and differentiation. 2009, Pubmed
Aruga, Zic1 promotes the expansion of dorsal neural progenitors in spinal cord by inhibiting neuronal differentiation. 2002, Pubmed
Avilion, Multipotent cell lineages in early mouse development depend on SOX2 function. 2003, Pubmed
Bani-Yaghoub, Role of Sox2 in the development of the mouse neocortex. 2006, Pubmed
Bellefroid, Xiro3 encodes a Xenopus homolog of the Drosophila Iroquois genes and functions in neural specification. 1998, Pubmed , Xenbase
Bergsland, The establishment of neuronal properties is controlled by Sox4 and Sox11. 2006, Pubmed
Bergsland, Sequentially acting Sox transcription factors in neural lineage development. 2011, Pubmed
Bhattaram, Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. 2010, Pubmed
Brault, Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. 2001, Pubmed
Brewster, Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. 1998, Pubmed , Xenbase
Bylund, Vertebrate neurogenesis is counteracted by Sox1-3 activity. 2003, Pubmed
Chaddah, Clonal neural stem cells from human embryonic stem cell colonies. 2012, Pubmed
Chan, ADSC therapy in neurodegenerative disorders. 2014, Pubmed
Chng, SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. 2010, Pubmed
Collignon, A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2. 1996, Pubmed
Dahmane, The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. 2001, Pubmed
De Robertis, Dorsal-ventral patterning and neural induction in Xenopus embryos. 2004, Pubmed , Xenbase
Devine, Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. 2011, Pubmed
Eisaki, XSIP1, a member of two-handed zinc finger proteins, induced anterior neural markers in Xenopus laevis animal cap. 2000, Pubmed , Xenbase
Ellis, SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. 2004, Pubmed
Florio, Neural progenitors, neurogenesis and the evolution of the neocortex. 2014, Pubmed
Fuccillo, Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. 2006, Pubmed
Fujita, The discovery of the matrix cell, the identification of the multipotent neural stem cell and the development of the central nervous system. 2003, Pubmed
Gaiano, Radial glial identity is promoted by Notch1 signaling in the murine forebrain. 2000, Pubmed
Glavic, Xiro-1 controls mesoderm patterning by repressing bmp-4 expression in the Spemann organizer. 2001, Pubmed , Xenbase
Gomez-Skarmeta, Araucan and caupolican, two members of the novel iroquois complex, encode homeoproteins that control proneural and vein-forming genes. 1996, Pubmed
Graham, SOX2 functions to maintain neural progenitor identity. 2003, Pubmed
Greber, FGF signalling inhibits neural induction in human embryonic stem cells. 2011, Pubmed
Gómez-Skarmeta, Xiro, a Xenopus homolog of the Drosophila Iroquois complex genes, controls development at the neural plate. 1998, Pubmed , Xenbase
Gómez-Skarmeta, The Wnt-activated Xiro1 gene encodes a repressor that is essential for neural development and downregulates Bmp4. 2001, Pubmed , Xenbase
Hatakeyama, Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. 2004, Pubmed
Hyodo-Miura, Involvement of NLK and Sox11 in neural induction in Xenopus development. 2002, Pubmed , Xenbase
Imayoshi, bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. 2014, Pubmed
Ishibashi, Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. 1995, Pubmed
Kalani, Wnt-mediated self-renewal of neural stem/progenitor cells. 2008, Pubmed
Kishi, Requirement of Sox2-mediated signaling for differentiation of early Xenopus neuroectoderm. 2000, Pubmed , Xenbase
Klein, Conserved structural domains in FoxD4L1, a neural forkhead box transcription factor, are required to repress or activate target genes. 2013, Pubmed , Xenbase
Kroll, Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation. 1998, Pubmed , Xenbase
Kuo, Opl: a zinc finger protein that regulates neural determination and patterning in Xenopus. 1998, Pubmed , Xenbase
Levine, Proposal of a model of mammalian neural induction. 2007, Pubmed
Levine, Gene regulatory networks for development. 2005, Pubmed
Li, Generation of purified neural precursors from embryonic stem cells by lineage selection. 1998, Pubmed
Lim, Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo. 2011, Pubmed , Xenbase
Miyagi, Consequence of the loss of Sox2 in the developing brain of the mouse. 2008, Pubmed
Mizuseki, SoxD: an essential mediator of induction of anterior neural tissues in Xenopus embryos. 1998, Pubmed , Xenbase
Mizuseki, Xenopus Zic-related-1 and Sox-2, two factors induced by chordin, have distinct activities in the initiation of neural induction. 1998, Pubmed , Xenbase
Mizutani, Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. 2007, Pubmed
Molofsky, Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. 2005, Pubmed
Moody, On becoming neural: what the embryo can tell us about differentiating neural stem cells. 2013, Pubmed , Xenbase
Nakata, Xenopus Zic3, a primary regulator both in neural and neural crest development. 1997, Pubmed , Xenbase
Nakata, Xenopus Zic family and its role in neural and neural crest development. 1998, Pubmed , Xenbase
Neely, DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction. 2012, Pubmed
Neilson, Specific domains of FoxD4/5 activate and repress neural transcription factor genes to control the progression of immature neural ectoderm to differentiating neural plate. 2012, Pubmed , Xenbase
Nitta, XSIP1 is essential for early neural gene expression and neural differentiation by suppression of BMP signaling. 2004, Pubmed , Xenbase
Nitta, The N-terminus zinc finger domain of Xenopus SIP1 is important for neural induction, but not for suppression of Xbra expression. 2007, Pubmed , Xenbase
Ohtsuka, Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. 2001, Pubmed
Palma, Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. 2004, Pubmed
Penzel, Characterization and early embryonic expression of a neural specific transcription factor xSOX3 in Xenopus laevis. 1997, Pubmed , Xenbase
Rogers, Neural induction and factors that stabilize a neural fate. 2009, Pubmed , Xenbase
Rogers, Xenopus Sox3 activates sox2 and geminin and indirectly represses Xvent2 expression to induce neural progenitor formation at the expense of non-neural ectodermal derivatives. 2009, Pubmed , Xenbase
Rogers, Sox3 expression is maintained by FGF signaling and restricted to the neural plate by Vent proteins in the Xenopus embryo. 2008, Pubmed , Xenbase
Ross, Human-induced pluripotent stem cells: potential for neurodegenerative diseases. 2014, Pubmed
Sasai, Identifying the missing links: genes that connect neural induction and primary neurogenesis in vertebrate embryos. 1998, Pubmed
Schultz, Geminin-deficient neural stem cells exhibit normal cell division and normal neurogenesis. 2011, Pubmed , Xenbase
Seo, Geminin's double life: chromatin connections that regulate transcription at the transition from proliferation to differentiation. 2006, Pubmed
Seo, Geminin regulates neuronal differentiation by antagonizing Brg1 activity. 2005, Pubmed , Xenbase
Sheng, Churchill, a zinc finger transcriptional activator, regulates the transition between gastrulation and neurulation. 2003, Pubmed , Xenbase
Snir, Xenopus laevis POU91 protein, an Oct3/4 homologue, regulates competence transitions from mesoderm to neural cell fates. 2006, Pubmed , Xenbase
Spella, Geminin regulates cortical progenitor proliferation and differentiation. 2011, Pubmed
Spemann, Induction of embryonic primordia by implantation of organizers from a different species. 1923. 2001, Pubmed
Stern, Neural induction: old problem, new findings, yet more questions. 2005, Pubmed , Xenbase
Streit, Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo. 1998, Pubmed
Streit, Initiation of neural induction by FGF signalling before gastrulation. 2000, Pubmed
Sullivan, foxD5a, a Xenopus winged helix gene, maintains an immature neural ectoderm via transcriptional repression that is dependent on the C-terminal domain. 2001, Pubmed , Xenbase
Sun, Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. 2007, Pubmed
Taylor, Tcf- and Vent-binding sites regulate neural-specific geminin expression in the gastrula embryo. 2006, Pubmed , Xenbase
Tropepe, Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. 2001, Pubmed
Uwanogho, Embryonic expression of the chicken Sox2, Sox3 and Sox11 genes suggests an interactive role in neuronal development. 1995, Pubmed
Verschueren, SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5'-CACCT sequences in candidate target genes. 1999, Pubmed , Xenbase
Wang, Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones. 2006, Pubmed
Wegner, From stem cells to neurons and glia: a Soxist's view of neural development. 2005, Pubmed
Wegner, From head to toes: the multiple facets of Sox proteins. 1999, Pubmed
Wichterle, Directed differentiation of embryonic stem cells into motor neurons. 2002, Pubmed
Wilson, An early requirement for FGF signalling in the acquisition of neural cell fate in the chick embryo. 2000, Pubmed , Xenbase
Wood, Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. 1999, Pubmed
Yan, Microarray identification of novel downstream targets of FoxD4L1/D5, a critical component of the neural ectodermal transcriptional network. 2010, Pubmed , Xenbase
Yan, foxD5 plays a critical upstream role in regulating neural ectodermal fate and the onset of neural differentiation. 2009, Pubmed , Xenbase
Yellajoshyula, Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state. 2011, Pubmed
Yellajoshyula, Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis. 2012, Pubmed , Xenbase
Zappone, Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. 2000, Pubmed
Zechner, beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. 2003, Pubmed
de la Calle-Mustienes, Xiro homeoproteins coordinate cell cycle exit and primary neuron formation by upregulating neuronal-fate repressors and downregulating the cell-cycle inhibitor XGadd45-gamma. 2002, Pubmed , Xenbase