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...

Background: Dexamethasone frequently is used for treatment of ketosis in dairy cows, but its effects are not fully understood.Hypothesis: Dexamethasone treatment affects whole body insulin sensitivity. Animals: Twelve German Holstein cows, 2-4 weeks postpartum, 5 days after omentopexy to correct left abomasal displacement.Methods: Randomized, blinded, case-control study. Treatment with dexamethasone-21-isonicotinate (DG; 40 lg/kg IM; n = 6) or saline (control group [CG], 15 mL IM, n = 6) on day 0 (d0). Blood samples were obtained before (d0) and after treatment (d1 and d2), and analyzed for glucose, insulin, and nonesterified fatty acid (NEFA) concentrations. Hepatic triglycerides (TAG) were measured in liver samples taken on d0 and d2. Five consecutive hyperinsulinemic-euglycemic clamps (HEC-I-V; insulin dosages: 0.1, 0.5, 2, 5, 10 mU/kg/min, respectively) were performed on d1 and steady state glucose infusion rate (SSGIR), insulin concentration (SSIC), insulin sensitivity index (ISI = SSGIR/SSIC), and plasma NEFA concentration (SSNEFA) were assessed.Results: Compared with CG-cows, DG-cows on d1 had higher plasma glucose (P = .004) and insulin (P < .001) concentrations, decreased SSGIR (HEC-II, P = .002; HEC-IV, P = .033), ISI (HEC-I, P < .015; HEC-II, P = .004), and insulin-stimulated decrease in SSNEFA (HEC-II, P = .006; HEC-III, P = .01; HEC-IV, P = .003; HEC-V, P = .011). Decrease in hepatic TAG content in DG-cows was higher compared with CG-cows (P < .001).Conclusions and Clinical Importance: Dexamethasone decreases whole body insulin sensitivity and affects glucose and lipid metabolism in early lactating dairy cows.

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