Abstract
A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.
Highlights
Rare hereditary human syndromes characterized by extensive genetic and phenotypic heterogeneity are among the most difficult diseases to understand at a molecular mechanistic level, and research on such syndromes relies heavily on mimicking the underlying mutations in animal models [1,2,3,4,5]
Depletion of Cep63 or Cep152 results in centriolar loss rather than amplification [22, 23]. Consistent with these observations, we found that knockdown of Cep63 or Cep152 in Cep57+/+ Mouse embryonic fibroblasts (MEFs) increased the incidence of mitotic centrosomes with only 1 centriole, and there was no evidence of centrosome amplification (Supplemental Figure 5, A, D, and E, and data not shown)
Using genetically engineered mouse models and primary cells derived from these animals, here we report several important new insights into the biological functions of Cep57
Summary
Rare hereditary human syndromes characterized by extensive genetic and phenotypic heterogeneity are among the most difficult diseases to understand at a molecular mechanistic level, and research on such syndromes relies heavily on mimicking the underlying mutations in animal models [1,2,3,4,5]. One such example is mosaic-variegated aneuploidy (MVA) syndrome, in which biallelic mutations in BUB1B (encoding the protein BUBR1) [1], CEP57 [6], or TRIP13 [3] have been described. BUBR1 is a core component of the mitotic checkpoint, a surveillance mechanism that ensures proper attachment of meta-
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