The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.
KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar - ICBAS, 4050-313 Porto, Portugal.
Filipa
F
Franquinho
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.
Joana
J
Nogueira-Rodrigues
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.
Joana M
JM
Duarte
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.
Sofia S
SS
Esteves
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-22, USA.
Christin
C
Carter-Su
The Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.|Office of the President, Ballou Hall, Tufts University, Medford, MA 02155, USA.
Anthony P
AP
Monaco
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.
Zoltán
Z
Molnár
The Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
Antonio
A
Velayos-Baeza
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.
Pedro
P
Brites
Nerve Regeneration group, Instituto de Biologia Molecular e Celular - IBMC and Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal.
Mónica M
MM
Sousa
D000375:Aging / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D049108:Cell Enlargement; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000071446:Neuronal Outgrowth; D009474:Neurons / Q000378:metabolism; D000072417:Protein Domains; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
D015815:Cell Adhesion Molecules; C500377:KIAA0319 protein, human; C000618031:KIAA0319 protein, mouse; D009419:Nerve Tissue Proteins; C582196:RGD1307443 protein, rat; D051899:Smad2 Protein; D053614:Janus Kinase 2
KIAA0319; Smad2; axon growth; axon regeneration; dyslexia