miR-375 inhibits differentiation of neurites by lowering HuD levels.
Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3' untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin alpha1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.
Abdelmohsen
Kotb
K
Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA. abdelmohsenk@grc.nia.nih.gov
Hutchison
Emmette R
ER
Lee
Eun Kyung
EK
Kuwano
Yuki
Y
Kim
Mihee M
MM
Masuda
Kiyoshi
K
Srikantan
Subramanya
S
Subaran
Sarah S
SS
Marasa
Bernard S
BS
Mattson
Mark P
MP
Gorospe
Myriam
M
D000818:Animals; D002460:Cell Line; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D000067779:ELAV-Like Protein 4; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D055495:Neurogenesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics
D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498011:Elavl4 protein, mouse; D035683:MicroRNAs; D012333:RNA, Messenger