Calmodulin-driven Nuclear Entry: Trigger for Sex Determination and Terminal Differentiation*

We originally proposed that Ca²⁺-calmodulin mediates a novel nuclear entry pathway distinct from the canonic Ran-dependent pathway (Sweitzer, T. D., and Hanover, J. A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 14574–14579). Although seemingly redundant, Ca²⁺-calmodulin-driven nuclear entry is now known to facilitate nuclear delivery of architectural transcription factors to chromatin. Intriguingly, defects in calmodulin-driven nuclear import of the transcription factors SRY and SOX9 in Sertoli cells lead to human sex reversal diseases with altered male gonad development. Calmodulin-triggered nuclear entry is an evolutionarily ancient feature of eukaryotes observed from yeast to man. Ca²⁺-calmodulin-triggered nuclear entry of key architectural transcription factors is a potentially key epigenetic regulator of terminal differentiation in response to cell signaling.