Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice

The ataxia telangiectasia mutant (ATM) protein is an intrinsic part of the cell cycle machinery that surveys genomic integrity and responses to genoto xic insult. Individuals with ataxia telangiectasia as well as Atm(-/-) mice are predisposed to cancer and are infertile due to spermatogenesis disrupt ion during first meiotic prophase. Atm(-/-) spermatocytes frequently displa y aberrant synapsis and clustered telomeres (bouquet topology). Here, we us ed telomere fluorescent in situ hybridization and immunofluorescence (IF) s taining of SCP3 and testes-specific histone H1 (H1t) to spermatocytes of At m- and Atm-p53-deficient mice and investigated whether gonadal atrophy in A tm-null mice is associated with stalling of telomere motility in meiotic pr ophase. SCP3-H1t IF revealed that most Atm(-/-) p53(-/-) spermatocytes dege nerated during late zygotene, while a few progressed to pachytene and diplo tene and some even beyond metaphase II, as indicated by the presence of a f ew round spermatids. In Atm(-/-) p53(-/-) meiosis, the frequency of spermat ocytes I with bouquet topology was elevated 72-fold. Bouquet spermatocytes with clustered telomeres were generally void of H1t signals, while mid-late pachytene and diplotene Atm(-/-) p53(-/-) spermatocytes displayed expressi on of H1t and showed telomeres dispersed over the nuclear periphery. Thus, it appears that meiotic telomere movements occur independently of ATM signa ling. Atm inactivation more likely leads to accumulation of spermatocytes I with bouquet topology by slowing progression through initial stages of fir st meiotic prophase and an ensuing arrest and demise of spermatocytes I. Se rtoli cells (SECs), which contribute to faithful spermatogenesis, in the At m mutants were found to frequently display numerous heterochromatin and tel omere clusters-a nuclear topology which resembles that of immature SECs. Ho wever, Atm(-/-) SECs exhibited a mature vimentin and cytokeratin 8 intermed iate filament expression signature. Upon IF with ATM antibodies, we observe d ATM signals throughout the nuclei of human and mouse SECs, spermatocytes I, and haploid round spermatids. ATM but not H1t was absent from elongating spermatid nuclei. Thus, ATM appears to be removed from spermatid nuclei pr ior to the occurrence of DNA nicks which emanate as a consequence of nucleo protamine formation.