The Mammalian Cervical Vertebrae Blueprint Depends on theT(brachyury) Gene

Abstract

A key common feature of all but three known mammalian genera is the strict seven cervical vertebrae blueprint, suggesting the involvement of strong conserving selection forces during mammalian radiation. This is further supported by reports indicating that children with cervical ribs die before they reach reproductive age. Hypotheses were put up, associating cervical ribs (homeotic transformations) to embryonal cancer (e.g., neuroblastoma) or ascribing the constraint in cervical vertebral count to the development of the mammalian diaphragm. Here, we describe a spontaneous mutation c.196A . G in the Bos taurus T gene (also known as brachyury) associated with a cervical vertebral homeotic transformation that violates the fundamental mammalian cervical blueprint, but does not preclude reproduction of the affected individual. Genome-wide mapping, haplotype tracking within a large pedigree, resequencing of target genome regions, and bioinformatic analyses unambiguously confirmed the mutant c.196G allele as causal for this previously unknown defect termed vertebral and spinal dysplasia (VSD) by providing evidence for the mutation event. The nonsynonymous VSD mutation is located within the highly conserved T box of the T gene, which plays a fundamental role in eumetazoan body organization and vertebral development. To our knowledge, VSD is the first unequivocally approved spontaneous mutation decreasing cervical vertebrae number in a large mammal. The spontaneous VSD mutation in the bovine T gene is the first in vivo evidence for the hypothesis that the T protein is directly involved in the maintenance of the mammalian seven-cervical vertebra blueprint. It therefore furthers our knowledge of the T-protein function and early mammalian notochord development.KEYWORDS homeotic transformation; genetic defect; brachyury H IGH evolutionary diversification of the vertebral column exists in vertebrates, but the number of cervical vertebrae within mammals has been fixed at seven for .200 million years of evolution since the beginning of the long and wide mammalian radiation (Hautier et al. 2010). The reason why all mammals share this fundamental blueprint of cervical vertebrae, compared with a more relaxed rule for the number of posterior vertebrae analogous to other nonmammalian vertebrates, remains unknown. Nevertheless, evolutionary and clinical data indicate that the cervical vertebral development of mammals is under high selection pressure. For example, in human pediatrics, 83% of children with a deviating number of cervical vertebrae die in their first year, while the surviving individuals do not reach reproductive age (Galis et al. 2006). A detailed knowledge of the key factors involved in the spatial regulation of vertebral development will help to understand these forces.Mutation models, either spontaneous or artificially induced, can reveal the complex processes that occur during vertebral development. Vertebral and accompanied spinal defects are described for many species, including cattle [e.g., complex vert...

Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China

“…43 A study in Bos taurus (cattle) also confirmed that a heterozygous mutation in Tbxt is causative for vertebral and spinal dysplasia phenotype, which is associated with a reduced number of cervical vertebrae. 44 These observations are consistent with the cervical vertebral fusion phenotype of our CS028 patient with p.R16L mutation. In humans, a homozygous missense TBXT mutation, p.H171R, has been previously identified in three families with a syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies.…”

T (brachyury) is linked to a Mendelian form of neural tube defects in humans

“…However, Postma and colleagues have recently reported on the involvement of T (brachyury) gene in the pathogenesis of an apparently monogenic form of NTD in humans encompassing sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal (Postma et al 2013). This is consistent with available data on the role of T in vertebral development (Ghebranious et al 2008;Kromik et al 2015). On the other hand, Kelley and colleagues reported in this journal an association between a common variant in T (rs2305089) and sporadic chordoma (Kelley et al 2014).…”

Vertebral and spinal dysplasia: A novel dominantly inherited congenital defect in Holstein cattle

“…In spite of the physical and functional dysfunctions associated with VSD in the hind limbs and in the vertebral column, there was no concomitant observation of urogenital or skull defects. Lack of urogenital or skull defects was confirmed in a further study focussing on detailed post-mortem analysis of VSD-affected calves (Kromik et al, 2015). This is a unique feature of VSD, because tail defects in other breeds or species are frequently associated with particular malformations as can be seen, for example, in CTS in Belgian Blue cattle (Fasquelle et al, 2009) and the well-known Manx syndrome in cats (Deforest and Basrur, 1979).…”