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Elucidating Regulatory Networks in Nervous System Development • How do embryonic cells acquire the ability to form different regions of the neural ectoderm? • How are embryonic neural stem cells established? • Can this information be used to direct ESCs to specific neural fates in vitro? Early Steps in Retinogenesis 1. Selection Maternal of VegT Competent and Vg1 inhibit Progenitors retina 2.Low Selection levels of Retina-Biased BMP signaling Progenitors • FGF3.signaling prevents Selection of • EphrinB1 signaling Retinal Stem Cellsvia the PCP(eye path promotes field) 4. Separation of Eye Fields NR 5. Regionalization Into Neural and Non-Neural Progenitor Pools Rx1 maintains 6. Neurogenesis retinal stem andcells Pax6Determination promotes celloftype Restricted biased progenitor Progenitors cells Neurotransmitter subtypes of amacrine cells 7. Cell Type Differentiation have different lineages Steps in Central Nervous System Development Neural Induction organizer Noggin, Chordin, Follistatin FGF, IGF Stabilization of Neural Fate Neural plate Sox, Zic, Iro, Gem AnteriorPosterior Axis Regional Identity A F M H P Sc FGF, Wnt RA Emx, Otx FGF,En,Wnt Krox, Hox Shh/BMP Cell Fate Specification bHLH genes (Ash, Ngn, NeuroD) TFs involved in neural-fate stabilization Organizer Neural Induction Stabilization early late Chordin Noggin Follistatin Geminin Siamois Differentiation Iro3 Ngn Zic1, 3 Other bHLH factors SoxD Sox2, 3 Iro1, 2 Cerberus Zic2 FoxD5 Ash 1. FoxD5 is expressed in the early neural plate 10.5 3. FoxD5 loss-of-function reduces the neural plate Sox3 ISH 2. FoxD5 over-expression expands the neural ectoderm control foxD5 100pg foxD5 250pg 4. FoxD5 over-expression represses bHLH differentiation genes Proposed Gene Regulatory Pathway by which FoxD5 Represses the Onset of Differentiation Sox3 FoxD5 Zic2 Zic1 Early-expressed neural genes Lateexpressed neural genes bHLH factors FoxD5 may be important for maintaining neural plate stem cells FoxD5 also increases proliferation of embryonic cells Embryonic origins of the vertebrate nervous system Neural plate: Neural crest: Cranial ganglia Spinal ganglia Autonomic ganglia Enteric ganglia Cranial cartilage Melanocytes FoxD5 Neural plate CNS Nc Placodes: Six1 Olfactory Lens Inner ear Cranial ganglia Secretory neurons Lateral line Initial induction of the pre-placodal ectoderm (1) Six1 expression is activated by low levels of neural inducers in the absence of Wnt and FGF signaling (2) Six1 promotes a placode fate at the expense of neural crest and epidermis FoxD5 Neural plate FoxD3 Neural crest sox11, six2, six4, eya1 Six1 Placode sox2, sox3, ngn1, neuroD Foxi1 Dlx5,6 Epidermis Six1 is involved in a GRN that establishes ectodermal domains Six1 promotes early placode genes to establish fate and promotes cell proliferation, but it represses differentiation genes • FoxD5 is an upstream TF in the early neural plate GRN • Six1 is an upstream TF in the placode GRN • Both promote immature stem or progenitor states by increasing proliferation and repressing differentiation genes Petra Pandur (Six1) Samantha Brugmann (Six1) Tammy Awtry (Six1) Himani Datta (Six1) Melissa Davis (Six1) Steve Sullivan (FoxD5) Latania Akers (FoxD5) Rakhee Goel (FoxD5) Karen Neilson (Six1 & FoxD5) Bo Yan (Six1, FoxD5, gene chips) • Interactions between GRNs in the different ectodermal domains establish and maintain the boundaries of these domains • Understanding the GRNs that regulate early neural fates will be important for engineering cells for tissue regeneration