The immunoglobulin-like superfamily member IGSF3 is a developmentally regulated protein that controls neuronal morphogenesis.
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. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 75-92, 2017.
Team Mice, Molecules and Synapse Formation, CIRB, Collège de France, CNRS, INSERM, PSL* Research University, Paris, France, 75231, Cedex 05.
Alessia
A
Usardi
Team Mice, Molecules and Synapse Formation, CIRB, Collège de France, CNRS, INSERM, PSL* Research University, Paris, France, 75231, Cedex 05.
Keerthana
K
Iyer
Team Mice, Molecules and Synapse Formation, CIRB, Collège de France, CNRS, INSERM, PSL* Research University, Paris, France, 75231, Cedex 05.
Séverine M
SM
Sigoillot
Team Mice, Molecules and Synapse Formation, CIRB, Collège de France, CNRS, INSERM, PSL* Research University, Paris, France, 75231, Cedex 05.
Antoine
A
Dusonchet
Team Mice, Molecules and Synapse Formation, CIRB, Collège de France, CNRS, INSERM, PSL* Research University, Paris, France, 75231, Cedex 05.
Fekrije
F
Selimi
D000818:Animals; D018929:Cell Culture Techniques; D002531:Cerebellum / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007136:Immunoglobulins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
C115741:IGSF3 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins
 development; Ig domains; cell adhesion molecules; cerebellum; neuronal morphogenesis