Ein MCPH1-vermitteltes Netzwerk reguliert die Neurogenese und das Schicksal neuronaler Stammzellen
Entwicklungsbiologie
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zellbiologie
Zusammenfassung der Projektergebnisse
Autosomal recessive primary microcephaly (MCPH, OMIM251200) is a neurodevelopmental disorder, characterized by a small head present at birth and a substantial reduction in size of the cerebral cortex, without apparent neurological structural anomalies. So far, 29 gene loci have been identified to be responsible for MCPH. MCPH1 is the first gene identified among MCPH-related genes and is one of the most commonly mutated MCPH genes responsible for primary microcephaly type 1 (MCPH1). Interestingly, MCPH1 mutations have also been found in a disorder called premature chromosome condensation syndrome (PCC) (OMIM606858). MCPH1 is a multifaceted protein and has been implicated in various and important cellular processes, including DNA damage response (DDR), cell cycle control, chromatin remodeling and tumorigenesis. Animal model studies have demonstrated the role of MCPH1 in brain development and PCC, as well as fertility. Our recent study showed that a deletion of the N-terminal domain, where most MCPH1 mutations and variants are located, in a mouse model (MCPH1-BR1Δ), but retaining the rest of the MCPH1 protein, recapitulates completely the phenotypes of the MCPH1 complete knockout mouse model, including microcephaly, gonad atrophy and tumorigenesis. It is surprising to repetitively observe the infertility and gonad developmental defects in either entire MCPH1 deleted (MCPH1-Δ) or the N-terminal BRCT domain deleted (MCPH1-BR1Δ) mouse modes, because these have not been reported in MCPH1 patients. The near 100% penetrance of ovarian tumors is striking, yet consistent with the notion that MCPH1 is down-regulated or mutated in human cancer patients, although MCPH1 patients have not been reported to be cancer prone. Due to limited personnel and expertise, we did not characterize the reproductive and tumor phenotypes. Nevertheless, our studies suggest an important function for MCPH1 in reproductive organ development and tumorigenesis, beyond its well characterized function in neuroprogenitors and brain development. We still do not know why the N-terminal BRCT1 domain of MCPH1 is so important for particular organs (brain and gonads). We hypothesized that the cell-type specific factors that interact with (the N-terminal) MCPH1 might be decisive. We identified several novel partners that specifically interact with the N-terminal domain, for example, TCOF1, a nucleolar protein. We also found co-incidentally that ribosomal proteins and the structure of nucleoli are dysregulated and ribosomal RNA biogenesis is altered in MCPH1 mutant cells. These findings suggest ribosomal homeostasis as novel molecular determinants and cellular pathways in brain development. We believe that to disclose the function of MCPH1-TCOF1 would benefit the understanding of etiological mechanisms not only in MCPH disorders, but also in the general brain development.
Projektbezogene Publikationen (Auswahl)
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Cell metabolic alterations due to Mcph1 mutation in microcephaly. Cell Reports 31(2):107506, 2020
Journiac, N., Gilabert-Juan, J., Cipriani, S., Benit, P., Liu, X., Jacquier, S., Faivre, V,. Delahaye-Duriez, A., Csaba, Z., Hourcade, T., Melinte, E., Lebon, S., Violle-Poirsier, C., Oury, J.-F., Adle-Biassette, H., Wang, Z.-Q., Mani1, S., Rustin, P., Gressens, P. & and Nardelli, J.
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MCPH1, beyond its role deciding the brain size. Aging (Albany NY). 13(20):23437-23439, 2021
Kristofova, M. & Wang, Z.-Q.
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The N-terminal BRCT domain determines MCPH1 function in brain development and fertility. Cell Death Disease 12(2):143, 2021
Liu, X., Schneble-Löhnert, N., Kristofova, M., Qing, X., Labisch, J., Hofmann, S., Ehrenberg, S., Sannai, M., Jörß, T., Ori, A., Godmann, M. & Wang, Z.-Q.
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Multifaceted microcephaly-related gene MCPH1. Cells 14;11(2):275, 2022
Kristofova, M. Ori, A. & Wang, Z.-Q.
