TY - JOUR
T1 - SRF phosphorylation by glycogen synthase kinase-3 promotes axon growth in hippocampal neurons
AU - Li, Cong L.
AU - Sathyamurthy, Aruna
AU - Oldenborg, Anna
AU - Tank, Dharmesh
AU - Ramanan, Narendrakumar
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Axon growth
KW - Filopodia
KW - GSK-3
KW - Neurite outgrowth
KW - Serum response factor
UR - http://www.scopus.com/inward/record.url?scp=84896754223&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896754223&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4677-12.2014
DO - 10.1523/JNEUROSCI.4677-12.2014
M3 - Article
C2 - 24623780
AN - SCOPUS:84896754223
SN - 0270-6474
VL - 34
SP - 4027
EP - 4042
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 11
ER -