Abnormalities of Limb Development in Vertebrate Animal Models of CdLS
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Abnormalities of Limb Development in Vertebrate Animal Models of CdLS

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Recent studies implicate the cohesin complex in transcriptional control, potentially through influences on long-distance communication between DNA elements. Animal models of Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy,” provide a unique opportunity to investigate both how cohesin regulates transcription, and the physiological consequences of disrupting that action. CdLS is most commonly caused by haploinsufficiency for NIPBL, a protein important for loading cohesin onto chromosomes, and individuals with CdLS frequently exhibit limb defects, particularly forelimb reductions of varying severity. Although Nipbl-deficient mice (Nipbl þ/ mice), display no gross limb abnormalities, we find that nipbl-deficient zebrafish exhibit severe reduction defects of the pectoral fins, the homologues of the mammalian forelimb. These defects are preceded by dysregulated expression of key developmental genes in the early limb (fin) bud, including fgfs in the apical ectodermal ridge; and shha, hand2, and hox genes in limb mesenchyme. Intriguingly, a strikingly similar pattern of gene expression changes can be detected in the limb buds of Nipbl-haploinsufficient mice, although the magnitude of gene expression changes is smaller. Limb bud-specific expression of Shh and Hox genes is known to be controlled by long-range enhancerpromoter interactions, and the pattern of changes in hox expression that occurs in Nipbl-deficient fin buds—characterized by downregulation of 5 0 hox genes and up-regulation of 3 0 hox genes—is consistent with the impairment of such long-range effects. Interestingly, knocking down expression of Med12—a subunit of the Mediator complex, which regulates promoter-enhancer communication and can co-localize with Nipbl on DNA—phenocopies morphological and transcriptional changes observed in Nipbldeficient fin buds. Moreover, partial reductions of Nipbl and Med12 interact synergistically, suggesting action in a common pathway. Overall, the data support the view that Nipbl and cohesin, most likely acting in concert with the Mediator complex, regulate limb-specific gene expression and limb development by influencing long-range chromosomal interactions, and suggest that these changes in expression in Nipbl-deficient limbs and fins are pathophysiologically significant in CdLS. Supported by NIH grant P01- HD052860 to ALC and ADL.

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