Spatial restriction of bone morphogenetic protein signaling in mouse gastrula through the mVam2-dependent endocytic pathway

Dev Cell. 2012 Jun 12;22(6):1163-75. doi: 10.1016/j.devcel.2012.05.009.


The embryonic body plan is established through positive and negative control of various signaling cascades. Late endosomes and lysosomes are thought to terminate signal transduction by compartmentalizing the signaling molecules; however, their roles in embryogenesis remain poorly understood. We showed here that the endocytic pathway participates in the developmental program by regulating the signaling activity. We modified the mouse Vam2 (mVam2) locus encoding a regulator of membrane trafficking. mVam2-deficient cells exhibited abnormally fragmented late endosomal compartments. The mutant cells could terminate signaling after the removal of the growth factors including TGF-β and EGF, except BMP-Smad1/Smad5 signaling. mVam2-deficient embryos exhibited ectopic activation of BMP signaling and disorganization of embryo patterning. We found that mVam2, which interacts with BMP type I receptor, is required for the spatiotemporal modulation of BMP signaling, via sequestration of the receptor complex in the late stages of the endocytic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Body Patterning / physiology
  • Bone Morphogenetic Protein Receptors, Type I / physiology
  • Bone Morphogenetic Proteins / physiology*
  • Endocytosis*
  • Endosomes / genetics
  • Endosomes / physiology
  • Epidermal Growth Factor / physiology
  • Gastrula / physiology*
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology
  • Genetic Loci
  • Mice
  • Signal Transduction / physiology*
  • Smad1 Protein / physiology
  • Smad5 Protein / physiology
  • Transforming Growth Factor beta / physiology
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / physiology*


  • Bone Morphogenetic Proteins
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Transforming Growth Factor beta
  • Vesicular Transport Proteins
  • Vps41 protein, mouse
  • Epidermal Growth Factor
  • Bone Morphogenetic Protein Receptors, Type I