Abstract
WDR62 is a scaffold protein involved in centriole duplication and spindle assembly during mitosis. Mutations in WDR62 can cause primary microcephaly and premature ovarian insufficiency. We have generated a genetrap mouse model deficient in WDR62 and characterised the developmental effects of WDR62 deficiency during meiosis in the testis. We have found that WDR62 deficiency leads to centriole underduplication in the spermatocytes due to reduced or delayed CEP63 accumulation in the pericentriolar matrix. This resulted in prolonged metaphase that led to apoptosis. Round spermatids that inherited a pair of centrioles progressed through spermiogenesis, however, manchette removal was delayed in WDR62 deficient spermatids due to delayed Katanin p80 accumulation in the manchette, thus producing misshapen spermatid heads with elongated manchettes. In mice, WDR62 deficiency resembles oligoasthenoteratospermia, a common form of subfertility in men that is characterised by low sperm counts, poor motility and abnormal morphology. Therefore, proper WDR62 function is necessary for timely spermatogenesis and spermiogenesis during male reproduction.
Highlights
WD40 repeat protein 62 (WDR62) is a scaffold protein involved in centriole duplication and spindle assembly during mitosis
Our studies showed that WDR62–Katanin interactions are required for efficient manchette removal
In our study, WDR62 deficiency in testes leads to oligoasthenoteratospermia, the most common cause of subfertility in man, characterised by low sperm counts, poor motility and abnormal sperm morphology
Summary
WDR62 is a scaffold protein involved in centriole duplication and spindle assembly during mitosis. We have found that WDR62 deficiency leads to centriole underduplication in the spermatocytes due to reduced or delayed CEP63 accumulation in the pericentriolar matrix. This resulted in prolonged metaphase that led to apoptosis. WD40 repeat protein 62 (WDR62) is a 166 kDa scaffold protein that associates with the centrosomes and spindle poles during mitosis. It is the second most commonly mutated gene in autosomal recessive primary microcephaly (MCPH)[4,5,6]. The C terminus of WDR62 contains serine/threonine phosphorylation motifs used for homodimerisation and heterodimerisation with its paralog, MAPKBP18, as well as interaction with kinases such as Aurora Kinase A (AURKA)[9] and c-Jun N-terminal kinase (JNK)[10]
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