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Cooperative activity of noggin and gremlin 1 in axial skeleton development

David A Stafford1, Lisa J Brunet, Mustafa K Khokha

  • 1Department of Molecular and Cell Biology and Center for Integrative Genomics, University of California, Berkeley, CA 94720, USA. dastaffo@berkeley.edu

Development (Cambridge, England)
|February 10, 2011
PubMed

Insights

BMP signaling inhibition by noggin (Nog) and gremlin 1 (Grem1) is crucial for sclerotome development. These BMP antagonists create a signaling-free zone, essential for hedgehog (Hh) signal-mediated sclerotome induction in mouse embryos.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Somite differentiation is initiated by inductive signals from adjacent tissues.
  • Bone morphogenetic protein (BMP) signaling plays a role in embryonic development.
  • Sclerotome specification is a critical step in axial skeleton formation.

Purpose of the Study:

  • To investigate the role of BMP signaling, specifically noggin (Nog) and gremlin 1 (Grem1), in sclerotome specification.
  • To determine the relationship between BMP signaling and hedgehog (Hh) signaling in sclerotome development.
  • To elucidate the mechanism by which BMP antagonists regulate sclerotome formation.

Main Methods:

  • Utilized mouse embryos with mutations in noggin (Nog) and gremlin 1 (Grem1).
  • Analyzed gene expression patterns for sclerotome (Pax1, Pax9) and dermomyotome (Pax3, Myf5, Lbx1) markers.
  • Employed conditional Bmpr1a mutation and BMP type I receptor inhibitor (dorsomorphin) treatment.
  • Investigated the interaction with hedgehog (Hh) signaling pathway components (smoothened - Smo).

Main Results:

  • Nog;Grem1 double mutants completely failed to initiate sclerotome development.
  • Nog mutants with reduced Grem1 showed a significant decrease in axial skeleton formation.
  • Dermomyotome induction occurred normally in Nog;Grem1 double mutants.
  • Inhibition of BMP signaling by dorsomorphin did not induce sclerotome markers.
  • Culturing Nog;Grem1 double mutants with dorsomorphin restored sclerotome development.
  • Hh signaling is necessary, as Pax1 expression in smoothened (Smo) mutants was not rescued by BMP inhibition.

Conclusions:

  • Noggin and gremlin 1 cooperate to establish a BMP signaling-free environment.
  • This BMP signaling-free zone is a prerequisite for Hh-mediated sclerotome induction.
  • BMP signaling acts permissively, not instructively, for sclerotome specification via Hh signaling.

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