The importance of cysteine cathepsin proteases for placental development.

The typically lysosomal family of cysteine cathepsin proteases has been implicated in the development of the placenta in particular, from studies in the mouse. Here, we analysed overall expression, regulation and presence of transcript isoforms of cysteine cathepsins during human extra-embryonic development. All 11 family members are expressed in human placental tissues, and many are differentially regulated during gestation.

Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development.

Establishment of the left-right axis is a fundamental process of vertebrate embryogenesis. Failure to develop left-right asymmetry leads to incorrect positioning and morphogenesis of numerous internal organs, and is proposed to underlie the etiology of several common cardiac malformations. The transcriptional modulator Cited2 is essential for embryonic development: Cited2-null embryos die during gestation with profound developmental abnormalities, including cardiac malformations, exencephaly and adrenal agenesis.

Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion.

EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established.

Cited1 is required in trophoblasts for placental development and for embryo growth and survival.

Cited1 is a transcriptional cofactor that interacts with Smad4, estrogen receptors alpha and beta, TFAP2, and CBP/p300. It is expressed in a restricted manner in the embryo as well as in extraembryonic tissues during embryonic development. In this study we report the engineering of a loss-of-function Cited1 mutation in the mouse.

Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells.

The CITED family proteins bind to CBP/p300 transcriptional integrators through their conserved C-terminal acidic domain and function as coactivators. The 21-kDa mouse Cited4 protein, a novel member of the CITED family, interacted with CBP/p300 as well as isoforms of the TFAP2 transcription factor, coactivating TFAP2-dependent transcription. The cited4 gene consisted of only a single exon located on chromosome 4 at 56.

Diverse requirements for Notch signalling in mammals.

The Notch signalling pathway has a central role in a wide variety of developmental processes and it is not therefore surprising that mutations in components of this pathway can cause dramatic human genetic disorders. One developmental process in which the Notch pathway is involved at multiple levels is somitogenesis, the mechanism by which the embryo is divided into segments that ultimately form structures such as the axial skeleton and skeletal muscle of the trunk. We are investigating the human genetic disorder spondylocostal dysplasia (SCD), which is a group of malsegmentation syndromes that occur when this process is disrupted.