Alix is required during development for normal growth of the mouse brain.
Alix (ALG-2 interacting protein X) drives deformation and fission of endosomal and cell surface membranes and thereby intervenes in diverse biological processes including cell proliferation and apoptosis. Using embryonic fibroblasts of Alix knock-out mice, we recently demonstrated that Alix is required for clathrin-independent endocytosis. Here we show that mice lacking Alix suffer from severe reduction in the volume of the brain which affects equally all regions examined. The cerebral cortex of adult animals shows normal layering but is reduced in both medio-lateral length and thickness. Alix controls brain size by regulating its expansion during two distinct developmental stages. Indeed, embryonic surface expansion of the Alix ko cortex is reduced because of the loss of neural progenitors during a transient phase of apoptosis occurring between E11.5 and E12.5. Subsequent development of the Alix ko cortex occurs normally until birth, when Alix is again required for the post-natal radial expansion of the cortex through its capacity to allow proper neurite outgrowth. The need of Alix for both survival of neural progenitor cells and neurite outgrowth is correlated with its role in clathrin-independent endocytosis in neural progenitors and at growth cones. Thus Alix-dependent, clathrin independent endocytosis is essential for controlling brain size.
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Marine H
MH
Laporte
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Christine
C
Chatellard
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Victoria
V
Vauchez
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Fiona J
FJ
Hemming
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Jean-Christophe
JC
Deloulme
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Frédérique
F
Vossier
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Béatrice
B
Blot
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Sandrine
S
Fraboulet
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, F-38042 Grenoble, France.|Université Grenoble Alpes, Institut des Neurosciences, F-38042 Grenoble, France.
Rémy
R
Sadoul
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002452:Cell Count; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004705:Endocytosis; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008831:Microcephaly / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism; D009929:Organ Size; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; C492144:Pdcd6ip protein, mouse; D005346:Fibroblast Growth Factors