Developmental perspectives on copy number abnormalities of the 22q11.2 region

The 22q11.2 chromosomal landscape predisposes to genomic rearrangements that are associated with a variety of clinical phenotypes. The most well known of these include the 22q11.2 deletion and Cat-eye syndromes (CES), but more recently other copy number abnormalities have been recognised, especially with increased use of microarrays in the investigation of patients with congenital malformations or cognitive impairment. In addition, mutations in the TBX1 gene have been found in patients with phenotypes reminiscent of 22q11.2 syndromes. Recent advances in our understanding of 22q11.2 genes and their interactions provide insight into the mechanisms underlying the phenotypic variability of the 22q11.2 syndromes, and suggest a possible common developmental pathway perturbed by copy number abnormalities of this locus. © 2010 John Wiley & Sons A/S.link_to_subscribed_fulltex

Long-range regulation at the SOX9 locus in development and disease

The involvement of SOX9 in congenital skeletal malformation was demonstrated 15 years ago with the identification of mutations in and around the gene in patients with campomelic dysplasia (CD). Translocations upstream of the coding sequence suggested that altered expression of SOX9 was capable of severely impacting on skeletal development. Subsequent studies in humans and animal models pointed towards a complex regulatory region controlling SOX9 transcription, involving ∼1 Mb of upstream sequence. Recent data indicate that this regulatory domain may extend substantially further, with identification of several disruptions greater than 1 Mb upstream of SOX9 associated with isolated Pierre Robin sequence (PRS), a craniofacial disorder that is frequently a component of CD. The translocation breakpoints upstream of SOX9 can now be clustered into three groups, with a trend towards less severe skeletal phenotypes as the distance of each cluster from SOX9 increases. In this review we discuss how the identification of novel lesions surrounding SOX9 support the existence of tissue specific enhancers acting over a large distance to regulate expression of the gene during craniofacial development, and we highlight the potential for discovery of additional regulatory elements within the extended SOX9 control region.link_to_subscribed_fulltex

Co-option of the cardiac transcription factor Nkx2.5 during development of the emu wing

The ratites are a distinctive clade of flightless birds, typified by the emu and ostrich that have acquired a range of unique anatomical characteristics since diverging from basal Aves at least 100 million years ago. The emu possesses a vestigial wing with a single digit and greatly reduced forelimb musculature. However, the embryological basis of wing reduction and other anatomical changes associated with loss of flight are unclear. Here we report a previously unknown co-option of the cardiac transcription factor Nkx2.5 to the forelimb in the emu embryo, but not in ostrich, or chicken and zebra finch, which have fully developed wings. Nkx2.5 is expressed in emu limb bud mesenchyme and maturing wing muscle, and mis-expression of Nkx2.5 throughout the limb bud in chick results in wing reductions. We propose that Nkx2.5 functions to inhibit early limb bud expansion and later muscle growth during development of the vestigial emu wing.The transcription factor Nkx2.5 is essential for heart development. Here, the authors identify a previously unknown expression domain for Nkx2.5 in the emu wing and explore its role in diminished wing bud development in the flightless emu, compared with three other birds that have functional wings