Targeted inactivation of nuclear interaction partner of ALK disrupts meiotic prophase.
NIPA (nuclear interaction partner of ALK) is an F-box-like protein that monitors the timing of mitotic entry. Constitutively active NIPA delays mitotic entry by preventing accumulation of nuclear cyclin B1. Here, we have investigated the consequences of Nipa inactivation by using a conditional knockout strategy. Nipa-deficient animals are viable but show a lower birth rate and reduced body weight. Furthermore, Nipa-deficient males are sterile owing to a block of spermatogenesis during meiotic prophase. Whereas Nipa-/- mouse embryonic fibroblasts show no severe phenotype, Nipa-/- spermatocytes arrest during stage IV of the epithelial cycle with subsequent TUNEL-positive apoptosis resulting from improper synapsis, defects in the repair of DNA double-stranded breaks and synaptonemal complex formation. Moreover, we show nuclear accumulation of cyclin B1 with a subsequent premature increase in G2/M kinase activity in Nipa-/- spermatocytes. Together, these results reveal a novel role for NIPA in meiosis.
Department of Internal Medicine III, Technical University of Munich, Munich 81675,  Germany.
Anna Lena
AL
Illert
Hiroyuki
H
Kawaguchi
Cristina
C
Antinozzi
Florian
F
Bassermann
Letitia
L
Quintanilla-Martinez
Christine
C
von Klitzing
Mitsuteru
M
Hiwatari
Christian
C
Peschel
Dirk G
DG
de Rooij
Stephan W
SW
Morris
Marco
M
Barchi
Justus
J
Duyster
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008540:Meiosis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013090:Spermatocytes / Q000378:metabolism
C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; C477289:NIPA protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering