Eigenschaften und Funktion Keimbahn spezifischer Lamine
Zusammenfassung der Projektergebnisse
Despite the fact that there is no higher eukaryotic life without gametogenesis, the molecular mechanisms required for generation of haploid fertilization competent gamets are largely unknown. Most pivotal questions such as how homologous chromosomes find and pair with each other, a fundamental prerequisite for recombination and segregation of the homologs during meiosis, are still open. Likewise, it is not known how the initial round spermatid nuclei shape into their characteristic flattened and elongated form. In this context, we were quite interested in elucidating the function of the nuclear envelope (NE) and its components during these most central meiotic and postmeiotic events. A major focus of the current project was set on the role of germ cell-specific lamins and their interacting partners in meiotic chromosome dynamics and nuclear remodelling and shaping during sperm head formation; respectively. By use of genetic as well as different cell biological approaches we could substantiate that germ cell-specific lamin C2 at least in the male is an essential determinant for meiotic genome haploidization. Absence of lamin C2 has severe consequences for male germ cell development in that it leads to a disruption of spermatogesis in meiotic prophase I. In particular, male lamin C2 knockout mice show massive failures in proper alignment, synapsis and recombination of the homologs leading to complete infertility. Further analysis revealed that lamin C2 most likely acts as local modulator of the NE to facilitate proper meiotic chromosome movement. With Sun2, a member of the recently discovered SUN-domain protein family, we could identify the first mammalian NE protein that is involved in tethering chromosomal ends to the NE. We demonstrated that Sun2 is part of a fibrillar transmembrane complex that links telomeres directly to the cytoskeleton This finding provided the very first direct evidence that meiotic telomere attachment and movement does not only correlate between the species on the cytological level, but is evolutionary conserved on the molecular level as well, a fact that in the meanwhile is proven by a variety of different studies from other groups. Another important aspect of the project was focused on the peculiarities and function of the NE during sperm head formation. We could show that mammalian sperm head formation involves different polarization of two novel spermiogenesis-specific LINC complexes. They consist of either Sun3/Nesprin1, which localizes to the posterior pole of the elongating spermatid, or Sun1η/Nesprin3 that remarkably polarizes to the opposite, i.e. anterior, pole. Strikingly, even though Sun domain proteins were defined as INM proteins, anterior Sun1η/Nesprin3 appeared not to be part of the NE, but rather showed an exceptional non-nuclear localization. This suggests that during sperm head formation LINC complexes occupy novel specific functions. In spite of that, our findings provide a first hint how spermatid nuclei could be anchored to cytoskeletal structures at opposite sides of the sperm head to enable its gradual shaping and elongation.
Projektbezogene Publikationen (Auswahl)
- (2007). Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope. Proc. Natl. Acad. Sci. USA 104: 7426-7431
Schmitt, J., Benavente, R., Hodzic, D., Höög, C., Stewart, C.L. and Alsheimer, M.
- (2009). Cohesin SMC1β protects telomeres in meiocytes. J. Cell Biol. 187: 185-199
Adelfalk, C., Janschek, J., Revenkova, E., Liebe, B., Göb, E., Alsheimer, M., Benavente, R., de Boer, E., Novak, I., Höög, C., Scherthan, H. and Jessberger, R.
- (2009). The dance floor of meiosis: Evolutionary conservation of nuclear envelope attachment and dynamics of meiotic telomeres. Genome Dyn. 5: 81-93
Alsheimer, M.
- (2010). Dynamic properties of meiosis-specific lamin C2 and its impact on nuclear envelope integrity. Nucleus 1: 273-283
Jahn, D., Schramm, S., Benavente, R. and Alsheimer, M.
- (2010). Mammalian sperm head formation involves different polarization of two novel LINC-complexes. PLoS ONE 5: e12072
Göb, E., Schmitt, J., Benavente, R. and Alsheimer, M.
