RegulationofSpermatogenesisbyCREM

The transcriptional regulator CREM plays a key role in spermatogenesis, acting as a central transcription factor triggering a cascade of transcriptional activation of post-meiotic genes involved in this process such as calspermin and testis angiotensin-converting enzyme. The key role of CREM in sperm formation is demonstrated by the male sterility of mice lacking CREM, the failure of spermatids to develop into mature sperm, and a lack of post-meiotic gene expression in these animals. Prior to meiosis, splice variants of CREM act as antagonists of cAMP-dependent transcriptional activation, but coordinate with spermatogenesis, the potent transcriptional activator CREM tau splice variant is highly expressed. In other tissues CREM activates genes in response to cAMP through phosphorylation and CBP association, but transcriptional activation by CREM in male germ cells is CBP independent. Stimulation of spermatids with follicle-stimulating hormone (FSH) induces cAMP formation, and the association of CREM with the coactivator ACT, although the mechanism regulating the interaction of CREM with ACT is not yet known. A two-hybrid screen looking for ACT interacting factors revealed another surprising component regulating CREM, the kinesin Kif17b. Kinesins are molecular motors that interact with microtubules to transport organelles and other material within the cell. Kif17b is actively exported from the nucleus in a Crm1-dependent manner, so when it is bound to ACT the export of Kif17b excludes CREM-ACT from the nucleus and blocks transcriptional activation by this complex. The mechanism regulating the interaction of Kif17b with ACT to drive CREM activation is not yet known. Although the regulation of transcription by a kinesin is surprising, a functional connection between cytoskeletal elements and transcriptional regulation is not unprecedented, as demonstrated by the transcription factor MIZ-1 that regulates transcription in response to changes in microtubule structure.

Contributor: Glenn Croston Ph.D.

REFERENCES: Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E, Schutz G. Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 1996 Mar 14;380(6570):162-5 De Cesare D, Fimia GM, Sassone-Corsi P. CREM, a master-switch of the transcriptional cascade in male germ cells. J Endocrinol Invest 2000 Oct;23(9):592-6 Fimia GM, De Cesare D, Sassone-Corsi P. CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 1999 Mar 11;398(6723):165-9 Fimia GM, Morlon A, Macho B, De Cesare D, Sassone-Corsi P. Transcriptional cascades during spermatogenesis: pivotal role of CREM and ACT. Mol Cell Endocrinol 2001 Jun 20;179(1-2):17-23 Foulkes NS, Mellstrom B, Benusiglio E, Sassone-Corsi P Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature 1992 Jan 2;355(6355):80-4 Foulkes NS, Schlotter F, Pevet P, Sassone-Corsi P. Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature 1993 Mar 18;362(6417):264-7 Macho B, Brancorsini S, Fimia GM, Setou M, Hirokawa N, Sassone-Corsi P. CREM-dependent transcription in male germ cells controlled by a kinesin. Science 2002 Dec 20;298(5602):2388-90 Nantel F, Monaco L, Foulkes NS, Masquilier D, LeMeur M, Henriksen K, Dierich A, Parvinen M, Sassone-Corsi P. Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 1996 Mar 14;380(6570):159-62 Ziegelbauer J, Shan B, Yager D, Larabell C, Hoffmann B, Tjian R. Transcription factor MIZ-1 is regulated via microtubule association. Mol Cell 2001 Aug;8(2):339-49