GDE3 regulates oligodendrocyte precursor proliferation via release of soluble CNTFRα

Author:

Dobrowolski Mateusz1,Cave Clinton12,Levy-Myers Reuben1,Lee ChangHee13,Park Sungjin14,Choi Bo-Ran1,Xiao Bo5ORCID,Yang Wanchun5,Sockanathan Shanthini1ORCID

Affiliation:

1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N Wolfe Street, PCTB 1004, Baltimore, MD 21205, USA

2. Middlebury College, Neuroscience Program, 276 Bicentennial Way, MBH 351, Middlebury, VT 05753, USA

3. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

4. University of Utah, BPRB 390D South 2030 East, Salt Lake City, UT 84112, USA

5. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China 610041

Abstract

Oligodendrocyte development is tightly controlled by extrinsic signals; however, mechanisms that modulate cellular responses to these factors remain unclear. Six-transmembrane glycerophosphodiester phosphodiesterases (GDEs) are emerging as central regulators of cellular differentiation via their ability to shed glycosylphosphatidylinositol (GPI)-anchored proteins from the cell surface. We show here that GDE3 controls the pace of oligodendrocyte generation by negatively regulating oligodendrocyte precursor cell (OPC) proliferation. GDE3 inhibits OPC proliferation by stimulating ciliary neurotrophic factor (CNTF)-mediated signaling through release of CNTFRα, the ligand-binding component of the CNTF-receptor multiprotein complex, which can function as a soluble factor to activate CNTF signaling. GDE3 releases soluble CNTFRα by GPI-anchor cleavage from the plasma membrane and from extracellular vesicles (EVs) after co-recruitment of CNTFRα in EVs. These studies uncover new physiological roles for GDE3 in gliogenesis and identify GDE3 as a key regulator of CNTF-dependent regulation of OPC proliferation through release of CNTFRα.

Funder

National Institutes of Health

Fulbright Association

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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