Smoothened Mutants Reveal Redundant Roles for Shh and Ihh Signaling Including Regulation of L/R Asymmetry by the Mouse Node

Cell. 2001 Jun 15;105(6):781-92.

Abstract

Genetic analyses in Drosophila have demonstrated that the multipass membrane protein Smoothened (Smo) is essential for all Hedgehog signaling. We show that Smo acts epistatic to Ptc1 to mediate Shh and Ihh signaling in the early mouse embryo. Smo and Shh/Ihh compound mutants have identical phenotypes: embryos fail to turn, arresting at somite stages with a small, linear heart tube, an open gut and cyclopia. The absence of visible left/right (L/R) asymmetry led us to examine the pathways controlling L/R situs. We present evidence consistent with a model in which Hedgehog signaling within the node is required for activation of Gdf1, and induction of left-side determinants. Further, we demonstrate an absolute requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis.[Dedicated to Rosa Beddington, a pioneer in mammalian embryology].

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Patterning
  • DNA-Binding Proteins*
  • Drosophila Proteins*
  • Embryo, Mammalian / embryology*
  • Embryo, Mammalian / metabolism
  • Embryonic Induction
  • Epistasis, Genetic
  • Gene Expression Regulation, Developmental
  • Growth Differentiation Factor 1
  • Growth Substances / genetics
  • Heart / embryology
  • Heart / physiology
  • Hedgehog Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins*
  • Membrane Proteins / genetics
  • Mice
  • Models, Biological
  • Muscle Proteins / genetics
  • Mutation / genetics*
  • Myogenic Regulatory Factor 5
  • Nerve Tissue Proteins / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled*
  • Signal Transduction
  • Smoothened Receptor
  • Somites / metabolism
  • Trans-Activators*
  • Transcription Factors / genetics
  • Xenopus Proteins*

Substances

  • CFC1 protein, human
  • Cfc1 protein, mouse
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Gdf1 protein, mouse
  • Growth Differentiation Factor 1
  • Growth Substances
  • Hedgehog Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Muscle Proteins
  • Myf5 protein, mouse
  • Myogenic Regulatory Factor 5
  • NKX2-5 protein, human
  • Nerve Tissue Proteins
  • Nkx2-5 protein, mouse
  • Patched Receptors
  • Patched-1 Receptor
  • Proteins
  • Ptch1 protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • SHH protein, human
  • Smo protein, mouse
  • Smoothened Receptor
  • Trans-Activators
  • Transcription Factors
  • Xenopus Proteins
  • smo protein, Drosophila