MEKK4 signaling regulates filamin expression and neuronal migration.
Periventricular heterotopia (PVH) is a congenital malformation of human cerebral cortex frequently associated with Filamin-A (FLN-A) mutations but the pathogenetic mechanisms remain unclear. Here, we show that the MEKK4 (MAP3K4) pathway is involved in Fln-A regulation and PVH formation. MEKK4(-/-) mice developed PVH associated with breaches in the neuroependymal lining which were largely comprised of neurons that failed to reach the cortical plate. RNA interference (RNAi) targeting MEKK4 also impaired neuronal migration. Expression of Fln was elevated in MEKK4(-/-) forebrain, most notably near sites of failed neuronal migration. Importantly, recombinant MKK4 protein precipitated a complex containing MEKK4 and Fln-A, and MKK4 mediated signaling between MEKK4 and Fln-A, suggesting that MKK4 may bridge these molecules during development. Finally, we showed that wild-type FLN-A overexpression inhibited neuronal migration. Collectively, our results demonstrate a link between MEKK4 and Fln-A that impacts neuronal migration initiation and provides insight into the pathogenesis of human PVH.
Sarkisian
Matthew R
MR
Department of Neurobiology and Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Bartley
Christopher M
CM
Chi
Hongbo
H
Nakamura
Fumihiko
F
Hashimoto-Torii
Kazue
K
Torii
Masaaki
M
Flavell
Richard A
RA
Rakic
Pasko
P
D000818:Animals; D000911:Antibodies, Monoclonal; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D003285:Contractile Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D018274:Electroporation; D005260:Female; D064448:Filamins; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D011247:Pregnancy; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology
D000911:Antibodies, Monoclonal; D000963:Antimetabolites; D003285:Contractile Proteins; D018076:DNA, Complementary; D064448:Filamins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D048768:MAP Kinase Kinase Kinase 4; C482780:Map3k4 protein, mouse; D001973:Bromodeoxyuridine