A nuclear actin function regulates neuronal motility by serum response factor-dependent gene transcription.
Neuronal motility relies on actin treadmilling. In addition to regulating cytoskeletal dynamics in the cytoplasm, actin modulates nuclear gene expression. We present a hitherto unappreciated cross talk of actin signaling with gene expression governing neuronal motility. Toward this end, we used a novel approach using mutant actins either favoring (G15S) or inhibiting (R62D) F-actin assembly. Overexpressing these mutant actins in mouse hippocampal neurons not only modulated growth-cone function but also neurite elongation, which was ambiguous by traditional pharmacological interference. G15S actin enhanced neurite outgrowth and filopodia number. In contrast, R62D reduced neurite length and impaired growth-cone filopodia formation. Growth-cone collapse induced by ephrin-As, a family of repulsive axon guidance molecules, is impaired upon R62D expression, resulting in perseverance of ring-shaped F-actin filaments. R62D-induced phenotypes strongly resemble neurons lacking SRF (Serum Response Factor). SRF controls gene transcription of various actin isoforms (e.g., Actb, Acta1) and actin-binding proteins (e.g., Gsn) and is the archetypical transcription factor to study actin interplay with transcription. We show that neuronal motility evoked by these actin mutants requires SRF activity. Further, constitutively active SRF partially rescues R62D-induced phenotypes. Conversely, actin signaling regulates neuronal SRF-mediated gene expression. Notably, a nucleus-resident actin (R62D(NLS)) also regulates SRF's transcriptional activity. Moreover, R62D(NLS) decreases neuronal motility similar to the cytoplasmic R62D actin mutant although R62D(NLS) has no access to cytoplasmic actin dynamics. Thus, herein we provide first evidence that neuronal motility not only depends on cytoplasmic actin dynamics but also on the availability of actin to modulate nuclear functions such as gene transcription.
Neuronal Gene Expression Laboratory, Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 15, Tübingen, Germany.
Sina
S
Stern
Evaine
E
Debre
Christine
C
Stritt
Jürgen
J
Berger
Guido
G
Posern
Bernd
B
Knöll
D000199:Actins / Q000502:physiology* / Q000648:ultrastructure; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology* / Q000648:ultrastructure; D020439:Growth Cones / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D000199:Actins; D026362:Serum Response Factor