title: SRF phosphorylation by glycogen synthase kinase-3 promotes axon growth in hippocampal neurons.
abstract: The growth of axons is an intricately regulated process involving intracellular signaling cascades and gene transcription. We had previously shown that the stimulus-dependent transcription factor, serum response factor (SRF), plays a critical role in regulating axon growth in the mammalian brain. However, the molecular mechanisms underlying SRF-dependent axon growth remains unknown. Here we report that SRF is phosphorylated and activated by GSK-3 to promote axon outgrowth in mouse hippocampal neurons. GSK-3 binds to and directly phosphorylates SRF on a highly conserved serine residue. This serine phosphorylation is necessary for SRF activity and for its interaction with MKL-family cofactors, MKL1 and MKL2, but not with TCF-family cofactor, ELK-1. Axonal growth deficits caused by GSK-3 inhibition could be rescued by expression of a constitutively active SRF. The SRF target gene and actin-binding protein, vinculin, is sufficient to overcome the axonal growth deficits of SRF-deficient and GSK-3-inhibited neurons. Furthermore, short hairpin RNA-mediated knockdown of vinculin also attenuated axonal growth. Thus, our findings reveal a novel phosphorylation and activation of SRF by GSK-3 that is critical for SRF-dependent axon growth in mammalian central neurons.
authors.affiliation: Department of Anatomy and Neurobiology and Department of Medicine, Division of Endocrinology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Cong L
authors.initials: CL
authors.lastname: Li
authors.forename: Aruna
authors.initials: A
authors.lastname: Sathyamurthy
authors.forename: Anna
authors.initials: A
authors.lastname: Oldenborg
authors.forename: Dharmesh
authors.initials: D
authors.lastname: Tank
authors.forename: Narendrakumar
authors.initials: N
authors.lastname: Ramanan
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics; D009474:Neurons / Q000201:enzymology / Q000648:ultrastructure; D010766:Phosphorylation / Q000502:physiology; D011554:Pseudopodia / Q000201:enzymology; D012694:Serine / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016596:Vinculin / Q000235:genetics / Q000378:metabolism
chemical_list: C511173:Mrtfa protein, mouse; C577485:Nes protein, mouse; D064231:Nestin; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C576273:myocardin-like protein 2, mouse; D016596:Vinculin; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3; axon growth; filopodia; neurite outgrowth; serum response factor