Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 20, Pages 7793-7798Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308025101
Keywords
spermatogenesis; spermiogenesis; ubiquitination; knockout; in silico subtraction
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Funding
- NICHD NIH HHS [U54 HD007495, P30 HD007495, HD07495, T32 HD007495] Funding Source: Medline
- NIGMS NIH HHS [GM07730, T32 GM007330] Funding Source: Medline
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We identified a testis-specific gene encoding a protein containing a BTB/POZ domain and six kelch repeats, which we named kelch (h) under bar omo (l) under bar og (10) under bar (KLHL10). KLHL10 displays high evolutionary conservation in mammals, as evidenced by 98.7% amino acid identity between mouse and human KLHL10. KLHL10 is exclusively expressed in the cytoplasm of elongating and elongated spermatids (steps 9-16). We generated a Klhl10 null allele in 129S6/SvEv mouse embryonic stem cells, and obtained 47 chimeras from six independent embryonic stem cell lines. Whereas low-percentage male chimeras only produce C57BL/6J offspring, high-percentage chimeric and heterozygous males were completely infertile because of disrupted spermiogenesis characterized by asynchronous spermatid maturation, degeneration of late spermatids, sloughing of postmeiotic germ cells from the seminiferous epithelium, and marked reduction in the numbers of late spermatids. Our data demonstrate that, like protamine-1 and -2, both alleles of Klhl10 are required for male fertility and that haploinsufficiency caused by a mutation in one allele of Klhl10 prevents genetic transmission of both mutant and WT alleles.
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