The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development.
Hedgehog (Hh) signaling is critical for patterning and growth during mammalian embryogenesis. Transcriptional profiling identified Growth-arrest-specific 1 (Gas1) as a general negative target of Shh signaling. Data presented here define Gas1 as a novel positive component of the Shh signaling cascade. Removal of Gas1 results in a Shh dose-dependent loss of cell identities in the ventral neural tube and facial and skeletal defects, also consistent with reduced Shh signaling. In contrast, ectopic Gas1 expression results in Shh-dependent cell-autonomous promotion of ventral cell identities. These properties mirror those of Cdo, an unrelated, cell surface Shh-binding protein. We show that Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development. Overall, these data support a new paradigm in Shh signaling whereby positively acting ligand-binding components, which are initially expressed in responding tissues to promote signaling, are then down-regulated by active Hh signaling, thereby modulating responses to ligand input.
Allen
Benjamin L
BL
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Tenzen
Toyoaki
T
McMahon
Andrew P
AP
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D018274:Electroporation; D047108:Embryonic Development / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D017931:DNA Primers; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C465570:Shh protein, mouse