Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation.
A central challenge in embryonic development is to understand how growth and pattern are coordinated to direct emerging new territories during morphogenesis. Here, we report on a signaling cascade that links cell proliferation and fate, promoting formation of a distinct progenitor domain within the developing chick hypothalamus. We show that the downregulation of Shh in floor plate-like cells in the forebrain governs their progression to a distinctive, proliferating hypothalamic progenitor domain. Shh downregulation occurs via a local BMP-Tbx2 pathway, Tbx2 acting to repress Shh expression. We show in vivo and in vitro that forced maintenance of Shh in hypothalamic progenitors prevents their normal morphogenesis, leading to maintenance of the Shh receptor, ptc, and preventing progression to an Emx2(+)-proliferative progenitor state. Our data identify a molecular pathway for the downregulation of Shh via a BMP-Tbx2 pathway and provide a mechanism for expansion of a discrete progenitor domain within the developing forebrain.
Manning
Liz
L
MRC Centre Development for Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2TN, UK.
Ohyama
Kyoji
K
Saeger
Bernhard
B
Hatano
Osamu
O
Wilson
Stuart A
SA
Logan
Malcolm
M
Placzek
Marysia
M
D000818:Animals; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000196:embryology* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000099260:Empty Spiracles Homeobox Proteins; C000606240:Ptch1 protein, mouse; C465570:Shh protein, mouse; C097348:T-Box Domain Protein 2