Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based

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Updated: Jul 10, 2026

Genetic Manipulation of Cerebellar Granule Neurons In Vitro and In Vivo to Study Neuronal Morphology and Migration
09:07

Genetic Manipulation of Cerebellar Granule Neurons In Vitro and In Vivo to Study Neuronal Morphology and Migration

Published on: March 17, 2014

Rubén Alvarez-Rodríguez1, Mercedes Barzi, Jordi Berenguer

  • 1Department of Cell Death and Proliferation, Institute for Biomedical Research of Barcelona, IIBB-CSIC-IDIBAPS, 08036 Barcelona, Spain.

The Journal of Biological Chemistry
|October 24, 2007
PubMed

Insights

Bone morphogenetic protein 2 (BMP2) inhibits Sonic hedgehog (Shh) driven proliferation in cerebellar cells by blocking Nmyc expression. The study identifies TIEG-1 as a key mediator, inducing cell cycle arrest and synergizing with BMP2 for differentiation.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Nmyc is a key regulator of cell cycle progression in cerebellar granular neuron precursors (CGNPs), mediating Sonic hedgehog (Shh) proliferative signals.
  • Ectopic Nmyc expression drives CGNP proliferation and can lead to tumorigenesis.
  • Bone morphogenetic protein 2 (BMP2) counteracts Shh by promoting cell cycle exit and differentiation in CGNPs.

Purpose of the Study:

  • To elucidate the molecular mechanism by which BMP2 antagonizes Shh-induced proliferation in CGNPs.
  • To identify the intermediary factor responsible for BMP2's inhibition of Nmyc expression.
  • To characterize the role of this intermediary factor in CGNP cell cycle control and differentiation.

Main Methods:

  • Investigated the interaction between BMP2, Shh, and Nmyc pathways in CGNPs.
  • Identified TIEG-1 (KLF10) as a crucial mediator using molecular assays.
  • Assessed the effects of TIEG-1 ectopic expression on CGNP cell cycle arrest, apoptosis, and differentiation.
  • Examined the synergistic effects of TIEG-1 with BMP2 and other differentiation factors.

Main Results:

  • BMP2 inhibits Shh-driven proliferation by suppressing Nmyc expression in CGNPs.
  • TIEG-1 (KLF10) was identified as the intermediary factor that blocks Nmyc expression via Sp1 sites in the Nmyc promoter.
  • Ectopic TIEG-1 expression induced cell cycle arrest and apoptosis in CGNPs but did not promote differentiation.
  • TIEG-1 synergized with BMP2 and other signals (dibutyryl cAMP) to promote terminal differentiation and prevent apoptosis in arrested cells.

Conclusions:

  • BMP2 signaling antagonizes Shh proliferative activity in CGNPs by downregulating Nmyc expression through the TIEG-1 mediator.
  • TIEG-1 plays a critical role in mediating BMP2-induced cell cycle exit.
  • BMP2 signaling coordinates cell cycle exit and differentiation as distinct but linked processes in CGNP development, with TIEG-1 acting as a key mediator of cell cycle arrest.

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