Ariel Ruiz i Altaba - US grants

Sonic hedgehog is required for the induction of ventral cell types in the neural tube, and in recent years for rapid progress has been made in understanding the signaling pathway for sonic hedgehog. Using Xenopus laevis as a model, the Principal Investigator's groups has shown that Gli genes, which encode zinc finger transcription factors with transient and graded expression in the neural plate or neural tube, are involved in this process. Specifically, Gli1 has been found to be necessary and sufficient for floor plate and ventral neuronal differentiation, whereas Gli2 and Gli3 appear to antagonize the effect of Gli1. In further studies of the roles of Gli genes in sonic hedgehog signaling and development of the neural tube, the Principal Investigator proposes several important and ambitious studies. He proposed to analyze the tissue and cellular localization of the Gli1 gene products, to carry out a structure/function analysis of gli proteins using site- directed mutagenesis, to make Gli1 or Gli3 transgenic mice as a natural extension of the frog studies, to further analyze the antagonize Gli1 function in the frogs, and finally to determine if Gli3 is required for dorsal neural tube cell determination.

DESCRIPTION: (adapted from the investigator's abstract) The goal of the project in this grant application is to understnad the molecular mechanisms underlying the development of basal cell cancer. Specifically, they focus their research in the potential role of Gli1 in inducing BCC development and in the understanding of the mechanisms regulated by this zinc finger transcription factor. They have previously shown that Gli1, but not Gli3, is consistently expressed in human sporadic BCCs and that it is sufficient to induce epidermal tumor formation in the skin of frog embryos. Because Gli1 is a target and mediator of Sonic hedgehog (Shh) signaling, Gli1 transcription represents the activation of the Shh signaling pathway. This is consistent with previous findings in which the gene Patched, encoding a transmembrane receptor for Shh having a negative effect on the pathway, is mutated in familial BCCs. Mutations in Patched are thought to be responsible for the Basal cell Nevus Syndrome. They propose to test for the role of Gli2 in BCC formation using the frog embryo assay and to test for the prevalence of its expression in sporadic human BCCs. In addition, they propose to develop a mouse model for BCC formation by the generation of an inducible Gli1 protein in transgenic mice. Finally, they propose to create an in vivo reporter assay for Gli1 function. The experiments are designed to provide a good model to study the molecular basis of BCC formation which may offer the opportunity to develop anti-cancer agents in the future. In addition, understanding how deregulation of the Shh signaling pathway and Gli1 function lead to BCC formation, will shed light into the normal role of this gene in follicle development.

DESCRIPTION: (adapted from the investigator's abstract) The goal of the project in this grant application is to understnad the molecular mechanisms underlying the development of basal cell cancer. Specifically, they focus their research in the potential role of Gli1 in inducing BCC development and in the understanding of the mechanisms regulated by this zinc finger transcription factor. They have previously shown that Gli1, but not Gli3, is consistently expressed in human sporadic BCCs and that it is sufficient to induce epidermal tumor formation in the skin of frog embryos. Because Gli1 is a target and mediator of Sonic hedgehog (Shh) signaling, Gli1 transcription represents the activation of the Shh signaling pathway. This is consistent with previous findings in which the gene Patched, encoding a transmembrane receptor for Shh having a negative effect on the pathway, is mutated in familial BCCs. Mutations in Patched are thought to be responsible for the Basal cell Nevus Syndrome. They propose to test for the role of Gli2 in BCC formation using the frog embryo assay and to test for the prevalence of its expression in sporadic human BCCs. In addition, they propose to develop a mouse model for BCC formation by the generation of an inducible Gli1 protein in transgenic mice. Finally, they propose to create an in vivo reporter assay for Gli1 function. The experiments are designed to provide a good model to study the molecular basis of BCC formation which may offer the opportunity to develop anti-cancer agents in the future. In addition, understanding how deregulation of the Shh signaling pathway and Gli1 function lead to BCC formation, will shed light into the normal role of this gene in follicle development.

Sonic hedgehog is required for the induction of ventral cell types in the neural tube, and in recent years for rapid progress has been made in understanding the signaling pathway for sonic hedgehog. Using Xenopus laevis as a model, the Principal Investigator's groups has shown that Gli genes, which encode zinc finger transcription factors with transient and graded expression in the neural plate or neural tube, are involved in this process. Specifically, Gli1 has been found to be necessary and sufficient for floor plate and ventral neuronal differentiation, whereas Gli2 and Gli3 appear to antagonize the effect of Gli1. In further studies of the roles of Gli genes in sonic hedgehog signaling and development of the neural tube, the Principal Investigator proposes several important and ambitious studies. He proposed to analyze the tissue and cellular localization of the Gli1 gene products, to carry out a structure/function analysis of gli proteins using site- directed mutagenesis, to make Gli1 or Gli3 transgenic mice as a natural extension of the frog studies, to further analyze the antagonize Gli1 function in the frogs, and finally to determine if Gli3 is required for dorsal neural tube cell determination.