Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches.

Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt͞␤-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt͞␤-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt͞␤-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.blastocyst ͉ uterus A crucial event during mammalian embryonic development is the process of implantation, during which the free-living blastocyst attaches to the uterine endometrium. Successful implantation depends on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus (1). For instance, blastocysts can only implant once they have been activated by uterine factor(s) that are regulated by ovarian steroid hormones (2). Conversely, expression of several uterine genes are regulated by a signal(s) emanating from activated blastocysts (3, 4). Multiple signaling pathways have been shown to participate in the implantation process, and several cytokines and growth factors have been shown to be expressed in the uterus at the time of implantation and to play important roles in this process (5). However, there is increasing evidence that members of other families of growth factors implicated in embryogenesis may also participate in the implantation process. It has been demonstrated that members of the hedgehog, bone morphogenetic, and Wnt proteins are expressed in the uterus at the time of implantation (6). However, the precise role of these different growth factor signaling pathways in the implantation process has not been determined. Furthermore, the cell types within the uterus that respond to these growth factors are not known. In this study, we set out to determine the role of the canonical Wnt͞␤-catenin signaling pathway in the implantation process. We demonstrate that this pathway is activated during two distinct stages before implantation. Signaling is transiently detected in circular smooth muscle forming a banding pattern of activity. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, we show that inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Materials and MethodsMating and Experimental Manipulation of Transgenic Animals. The generation and characterization of the TCF͞Lef-LacZ transgenic mice have been described in ...