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PhD Student, Johns Hopkins University Bloomberg School of Public Health

PINBOARD SUMMARY

Smc5/6 complex, along with cohesin (Smc1/3) and condensin (Smc2/4), is the least studied and characterized protein complex of three Structural Maintenance of Chromosomes (SMC) complexes responsible for chromosome architecture and dynamics. It plays a central role in maintaining genome integrity. Previous reports showed that mutations in the Smc5/6 complex cause severe developmental defects, including microcephaly and primordial dwarfism in humans. However, it is not known exactly how the loss of Smc5/6 disrupts the molecular pathways in the developing brain. We have developed a novel mutant mouse model harboring a conditional knock-out (cKO) allele of Smc5. These mice exhibit microcephaly during embryonic development through adulthood, thus mimicking the defect seen in humans. We confirm our previous observation that cKO of Smc5 results in the destabilization of the entire Smc5/6 complex. We compared brain morphology and neural stem cell status in Smc5 cKO and control mice during fetal development, neonatal development and adulthood. We found that Smc5 cKO mice had severely underdeveloped cerebral cortex and showed reduced numbers of neural stem cells and progenitors within the ventricular zone (VZ) and lower cortical layers (VI-IV), respectively. In our current work, we are closely assessing development of the fetal brain to determine the direct consequences of destabilizing the Smc5/6 complex. We are also assessing the genetic causes of the apoptotic response that leads to the development of microcephaly. Ultimately, our research will contribute to understanding of the molecular functions of the Smc5/6 complex during brain development in humans.

7 ITEMS PINNED

Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis suggests functions in distinct chromosome processes.

Abstract: Four members of the structural maintenance of chromosome (SMC) protein family have essential functions in chromosome condensation (SMC2/4) and sister-chromatid cohesion (SMC1/3). The SMC5/6 complex has been implicated in chromosome replication, DNA repair and chromosome segregation in somatic cells, but its possible functions during mammalian meiosis are unknown. Here, we show in mouse spermatocytes that SMC5 and SMC6 are located at the central region of the synaptonemal complex from zygotene until diplotene. During late diplotene both proteins load to the chromocenters, where they colocalize with DNA Topoisomerase IIα, and then accumulate at the inner domain of the centromeres during the first and second meiotic divisions. Interestingly, SMC6 and DNA Topoisomerase IIα colocalize at stretched strands that join kinetochores during the metaphase II to anaphase II transition, and both are observed on stretched lagging chromosomes at anaphase II following treatment with Etoposide. During mitosis, SMC6 and DNA Topoisomerase IIα colocalize at the centromeres and chromatid axes. Our results are consistent with the participation of SMC5 and SMC6 in homologous chromosome synapsis during prophase I, chromosome and centromere structure during meiosis I and mitosis and, with DNA Topoisomerase IIα, in regulating centromere cohesion during meiosis II.

Pub.: 12 Jul '13, Pinned: 22 Aug '17

The SMC5/6 complex is involved in crucial processes during human spermatogenesis.

Abstract: Genome integrity is crucial for safe reproduction. Therefore, chromatin structure and dynamics should be tightly regulated during germ cell development. Chromatin structure and function are in large part determined by the structural maintenance of chromosomes (SMC) protein complexes, of which SMC5/6 recently has been shown to be involved in both spermatogonial differentiation and meiosis during mouse spermatogenesis. We therefore investigated the role of this complex in human spermatogenesis. We found SMC6 to be expressed in the human testis and present in a subset of type Adark and type Apale spermatogonia, all spermatocytes, and round spermatids. During human meiosis, SMC5/6 is located at the synaptonemal complex (SC), the XY body, and at the centromeres during meiotic metaphases. However, in contrast to mouse spermatogenesis, SMC6 is not located at pericentromeric heterochromatin in human spermatogenic cells, indicating subtle but perhaps important differences in not only SMC5/6 function but maybe also in maintenance of genomic integrity at the repetitive pericentromeric regions. Nonetheless, our data clearly indicate that the SMC5/6 complex, as shown in mice, is involved in numerous crucial processes during human spermatogenesis, such as in spermatogonial development, on the SC between synapsed chromosomes, and in DNA double-strand break repair on unsynapsed chromosomes during pachynema.

Pub.: 24 May '14, Pinned: 22 Aug '17

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes.

Abstract: SMC complexes include three major classes: cohesin, condensin, and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis had not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre-driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase II alpha to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females.

Pub.: 18 Mar '17, Pinned: 22 Aug '17