Excellence in Research: Upstream and Downstream Analysis of Hoxa1 Gene Expression

Southern University, Baton Rouge LA

Investigators

Abstract

Hoxa1 is an important regulator of embryonic development in vertebrates. Studies have indicated that the lack of Hoxa1 in mouse embryos results in developmental defects, including hindbrain deficiencies, abnormal bone growth in the skull and, ultimately, in death. In humans, mutations in this gene result in neurological disorders and autism susceptibility. Conversely, elevated levels of Hoxa1 promote cell proliferation and cancer. These observations highlight the importance of Hoxa1 but little is known about the mechanism by which a precise control of Hoxa1 gene expression is achieved in cells. To shed light on this problem, this project will employ mouse Embryonic Stem cells in order to understand how the levels of Hoxa1 are controlled in cells. The project is an extension of preliminary findings in the Principal Investigator's laboratory which indicate that the Hoxa1 protein plays a role in controlling its own gene expression. Thus, the results from this project will lead to the elucidation of the specific roles played by Hoxa1 on the differentiation of ES cells, which will represent a significant contribution to the area of stem cell biology. In addition, a number of different sectors (research, industry, and education) will benefit from this study for more effective development of novel stem cell applications. The work includes a mentoring program for undergraduate students and therefore, will have broader impacts on the preparation of traditionally underrepresented students who wish to follow a scientific career in Biological Sciences. Hoxa1 is a transcription factor (TF) that plays an important role during development of the early brain and neural crest-derived structures in vertebrates. In humans, mutations in this gene are associated with various Central Nervous System (CNS) disorders and overexpression has been associated with cancer development. These observations highlight the importance of Hoxa1 for correct embryonic development and as a causative factor in human disorders and cancer. However, in spite of the recognized importance of Hoxa1 during vertebrate development, little is known about its molecular mechanism of action in cells and tissues. The goal of this work is to shed light on the molecular mechanisms of Hoxa1 transcriptional gene regulation and function. This will be accomplished by investigating a novel autoregulatory feedback mechanism uncovered by our laboratory and by examining the expression of putative Hoxa1 direct target genes during mouse ES cell differentiation both under two-dimensional (2D) and tri-dimensional (3D) culture conditions. The results from these studies will improve understanding of basic molecular mechanisms relevant to Developmental Biology, Organ and Tissue Replacement and Cancer Research, among others. This project is jointly funded by Historically Black Colleges and Universities Undergraduate Program and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.