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Katja Baur1, Şeydanur Şan1,2, Gabriele Hölzl-Wenig1

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Growth/differentiation factor 15 (GDF15) signaling regulates progenitor proliferation via primary cilia. GDF15 affects cilia morphology and sonic hedgehog (SHH) pathway activation, mediated by GFRAL localization within the cilium.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Growth/differentiation factor 15 (GDF15) and its receptor GFRAL regulate apical progenitor proliferation in the periventricular germinal epithelium.
  • The precise molecular mechanisms underlying GDF15-mediated regulation of progenitor proliferation remain largely unknown.

Purpose of the Study:

  • To elucidate the role of GDF15 and GFRAL in primary cilia and their impact on apical progenitor proliferation.
  • To investigate the molecular pathways, including histone deacetylase 6 (Hdac6) and adenylate cyclase 3 (Adcy3), involved in GDF15 signaling.

Main Methods:

  • Analysis of primary cilia morphology and GFRAL localization in GDF15-ablated progenitor cells.
  • Measurement of transcript levels for Hdac6 and Adcy3 in mutant progenitors.
  • Assessment of microtubule acetylation, sonic hedgehog (SHH) pathway activation, and ciliary ADCY3 levels.
  • Pharmacological intervention using GDF15, HDAC6 antagonists, and ADCY3 antagonists.

Main Results:

  • GDF15 ablation altered primary cilia morphology and increased Hdac6 and Adcy3 transcript levels in progenitors.
  • Microtubule acetylation, SHH signaling, and ciliary ADCY3 were affected by GDF15 ablation.
  • Exogenous GDF15 or pharmacological inhibition of HDAC6/ADCY3 normalized cilia, proliferation, and SHH signaling.
  • Ciliary GFRAL localization correlated with GDF15's effects on Hdac6 and cilia length in the periventricular niche, but not in the hippocampus.

Conclusions:

  • Ciliary GFRAL signaling is crucial for GDF15's effects on primary cilia elongation and apical progenitor proliferation.
  • GDF15 modulates progenitor proliferation through a mechanism involving primary cilia, Hdac6, Adcy3, and SHH signaling.
  • The specific niche and ciliary localization of GFRAL dictate the cellular response to GDF15.