SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules.
Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.
Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Daniel E
DE
Lysko
Mary
M
Putt
Jeffrey A
JA
Golden
D000199:Actins / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D000089662:Doublecortin Protein; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005829:Geniculate Bodies / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008870:Microtubules / Q000502:physiology*; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050257:Tubulin Modulators / Q000494:pharmacology
D000199:Actins; D054377:Chemokine CXCL12; C000714847:Dcx protein, mouse; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D050257:Tubulin Modulators; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
DCX; SDF1; cortactin; cytoskeleton; interneuron; migration