MeCP2 deficiency disrupts axonal guidance, fasciculation, and targeting by altering Semaphorin 3F function.
Rett syndrome (RTT) is an autism spectrum disorder that results from mutations in the transcriptional regulator methyl-CpG binding protein 2 (MECP2). In the present work, we demonstrate that MeCP2 deficiency disrupts the establishment of neural connections before synaptogenesis. Using both in vitro and in vivo approaches, we identify dynamic alterations in the expression of class 3 semaphorins that are accompanied by defects in axonal fasciculation, guidance, and targeting with MeCP2 deficiency. Olfactory axons from Mecp2 mutant mice display aberrant repulsion when co-cultured with mutant olfactory bulb explants. This defect is restored when mutant olfactory axons are co-cultured with wild type olfactory bulbs. Thus, a non-cell autonomous mechanism involving Semaphorin 3F function may underlie abnormalities in the establishment of connectivity with Mecp2 mutation. These findings have broad implications for the role of MECP2 in neurodevelopment and RTT, given the critical role of the semaphorins in the formation of neural circuits.
Degano
Alicia L
AL
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. adegano1@jhmi.edu
Pasterkamp
R Jeroen
RJ
Ronnett
Gabriele V
GV
D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology / Q000196:embryology; D009833:Olfactory Pathways / Q000033:anatomy & histology / Q000502:physiology; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000502:physiology; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D019147:Vomeronasal Organ / Q000033:anatomy & histology / Q000502:physiology
D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; C491229:Sema3f protein, mouse