The Meiotic Nuclear Lamina Regulates Chromosome Dynamics and Promotes Efficient Homologous Recombination in the Mouse

Abstract

The nuclear lamina is the structural scaffold of the nuclear envelope and is well known for its central role in nuclear organization and maintaining nuclear stability and shape. In the past, a number of severe human disorders have been identified to be associated with mutations in lamins. Extensive research on this topic has provided novel important clues about nuclear lamina function. These studies have contributed to the knowledge that the lamina constitutes a complex multifunctional platform combining both structural and regulatory functions. Here, we report that, in addition to the previously demonstrated significance for somatic cell differentiation and maintenance, the nuclear lamina is also an essential determinant for germ cell development. Both male and female mice lacking the short meiosis-specific A-type lamin C2 have a severely defective meiosis, which at least in the male results in infertility. Detailed analysis revealed that lamin C2 is required for telomere-driven dynamic repositioning of meiotic chromosomes. Loss of lamin C2 affects precise synapsis of the homologs and interferes with meiotic double-strand break repair. Taken together, our data explain how the nuclear lamina contributes to meiotic chromosome behaviour and accurate genome haploidization on a mechanistic level.

Repression of the soma-specific transcriptome by Polycomb-repressive complex 2 promotes male germ cell development

“…Lamin C2 is a meiotic-specific lamin transcribed from an alternative promoter at the Lmna locus, where the somatic lamin A and C promoters are normally associated with high levels of H3K27me3 in wild-type spermatocytes. It is therefore likely that ectopic expression of lamins A and C in mutant spermatocytes interferes with the function of lamin C2 in telomere-mediated rearrangement of meiotic chromosomes (Link et al 2013). These data are compatible with the model in which ectopic expression of somatic lamins in meiocytes impairs the hypermobility of the LINC complex, possibly through the interaction with SUN1.…”

“…Mammalian meiotic cells are distinguished by the absence of lamins A, C, and B2, which are typically expressed in differentiated somatic cells (Burke and Stewart 2013;Haque et al 2006;Link et al 2013). A-type lamins are encoded by Lmna genes and are composed of three isoforms, including somatic lamins A and C and meiotic lamin C2.…”

Brca2/Pds5 complexes mobilize persistent meiotic recombination sites to the nuclear envelope

“…This might include cohesins and lamins. For example, patients suffering from laminopathies like the Hutchison-Wilford progeria syndrome exhibit increased DNA damage sensitivity and high frequencies of ovarian cancer similar to carriers of mutations in Brca2 (Kudlow et al, 2007;Link et al, 2013). Given that meiotic homologous recombination can be relatively easily followed and manipulated in Drosophila germaria, future studies in flies might clarify whether the nuclear lamina indeed functions as a subnuclear compartment for homologous recombination.…”

“…Cohesins likely further stabilize homolog pairing, and most eukaryotes possess meiosis-specific cohesins (Dorsett and Ström, 2012). Many eukaryotes also have germline-specific lamins suggesting an involvement of the nuclear envelope in meiosis (Jahn et al, 2010;Link et al, 2013). The connections between homologous recombination, cohesins and lamins are currently mostly obscure.…”

Lamin A/C proteins in the spermatid acroplaxome are essential in mouse spermiogenesis

“…However Lmna K/K mice actually lack the expression of both meiosis-specific lamin C2 and somatic A-type lamins A and C and, as a consequence, show a strong somatic disease phenotype. Then a lamin C2 isoformspecific knockout model was generated and the results demonstrate that lamin C2 contributes directly to fertility through facilitation of meiotic chromosome movements (Link et al 2013). Due to incomplete meiosis, Lmna K/K mice are unable to generate haploid spermatids.…”