GDF15 controls primary cilia morphology and function thereby affecting progenitor proliferation.

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.