The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development (original) (raw)

  1. Benjamin L. Allen1,
  2. Toyoaki Tenzen2, and
  3. Andrew P. McMahon1,3
  4. 1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA;
  5. 2 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

Abstract

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.

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