A novel Hap1-Tsc1 interaction regulates neuronal mTORC1 signaling and morphogenesis in the brain.
Tuberous sclerosis complex (TSC) is a leading genetic cause of autism. The TSC proteins Tsc1 and Tsc2 control the mTORC1 signaling pathway in diverse cells, but how the mTORC1 pathway is specifically regulated in neurons remains to be elucidated. Here, using an interaction proteomics approach in neural cells including neurons, we uncover the brain-enriched protein huntingtin-associated protein 1 (Hap1) as a novel functional partner of Tsc1. Knockdown of Hap1 promotes specification of supernumerary axons in primary hippocampal neurons and profoundly impairs the positioning of pyramidal neurons in the mouse hippocampus in vivo. The Hap1 knockdown-induced phenotypes in primary neurons and in vivo recapitulate the phenotypes induced by Tsc1 knockdown. We also find that Hap1 knockdown in hippocampal neurons induces the downregulation of Tsc1 and stimulates the activity of mTORC1, as reflected by phosphorylation of the ribosomal protein S6. Inhibition of mTORC1 activity suppresses the Hap1 knockdown-induced polarity phenotype in hippocampal neurons. Collectively, these findings define a novel link between Hap1 and Tsc1 that regulates neuronal mTORC1 signaling and neuronal morphogenesis, with implications for our understanding of developmental disorders of cognition.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Luis A
LA
Mejia
Nadia
N
Litterman
Yoshiho
Y
Ikeuchi
Luis
L
de la Torre-Ubieta
Eric J
EJ
Bennett
Chi
C
Zhang
J Wade
JW
Harper
Azad
A
Bonni
D000818:Animals; D001921:Brain / Q000254:growth & development*; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C490758:Hap1 protein, mouse; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases