Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4.
Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distribution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix. Elongating spermatids are not transcriptionally active, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targeted deletion of the gene Camk4. Male Camk4-/- mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of transition protein-2 (Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signalling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertility.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
J Y
JY
Wu
T J
TJ
Ribar
D E
DE
Cummings
K A
KA
Burton
G S
GS
McKnight
A R
AR
Means
D000595:Amino Acid Sequence; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011479:Protamines / Q000235:genetics / Q000378:metabolism; D013076:Sperm Count; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D013737:Testis / Q000254:growth & development / Q000378:metabolism
D009687:Nuclear Proteins; D011479:Protamines; C068621:protamine 2; C026588:sperm basic nuclear proteins; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse