Journal
DEVELOPMENTAL NEUROBIOLOGY
Volume 77, Issue 1, Pages 75-92Publisher
WILEY-BLACKWELL
DOI: 10.1002/dneu.22412
Keywords
development; cerebellum; cell adhesion molecules; Ig domains; neuronal morphogenesis
Categories
Funding
- Investissements d'Avenir
- ANR [ANR-10-LABX-54 MEMO LIFE]
- Fondation Bettencourt Schuller
- Ecole des Neurosciences de Paris
- Emergence UPMC
- Association Francaise du Syndrome de Rett
- ATIP-AVENIR
- FENS Boehringer Ingelheim
- Fondation pour la Recherche Medicale
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The establishment of a functional brain depends on the fine regulation and coordination of many processes, including neurogenesis, differentiation, dendritogenesis, axonogenesis, and synaptogenesis. Proteins of the immunoglobulin-like superfamily (IGSF) are major regulators during this sequence of events. Different members of this class of proteins play nonoverlapping functions at specific developmental time-points, as shown in particular by studies of the cerebellum. We have identified a member of the little studied EWI subfamily of IGSF, the protein IGSF3, as a membrane protein expressed in a neuron specific-and time-dependent manner during brain development. In the cerebellum, it is transiently found in membranes of differentiating granule cells, and is particularly concentrated at axon terminals. There it co-localizes with other IGSF proteins with well-known functions in cerebellar development: TAG-1 and L1. Functional analysis shows that IGSF3 controls the differentiation of granule cells, more precisely axonal growth and branching. Biochemical experiments demonstrate that, in the developing brain, IGSF3 is in a complex with the tetraspanin TSPAN7, a membrane protein mutated in several forms of X-linked intellectual disabilities. In cerebellar granule cells, TSPAN7 promotes axonal branching and the size of TSPAN7 clusters is increased by downregulation of IGSF3. Thus IGSF3 is a novel regulator of neuronal morphogenesis that might function through interactions with multiple partners including the tetraspanin TSPAN7. This developmentally regulated protein might thus be at the center of a new signaling pathway controlling brain development. VC 2016 Wiley Periodicals, Inc.
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