Dr. William H. Klein
The University of Texas M. D. Anderson Cancer Center
Department of Biochemistry and Molecular Biology
- Gene regulatory networks
- Systems biology
- Cell differentiation
- Mouse genetic models
During development, multipotent progenitor cells differentiate into specific cell types. An individual cell fate relies on the progenitor cell’s external environment and its internal genetic program at any given moment in time. My laboratory is investigating how gene expression programs are regulated when progenitor cells differentiate into individual cell types. We are especially interested in the role of cell-type specific transcription factors and their ability to alter programs of gene expression. We use diverse models to delineate how particular transcription factors work to program cellular differentiation. In one project, we have identified some of the key transcription factors that regulate the differentiation of the ganglion cells of the mouse neural retina. Retinal ganglion cells are responsible for transmitting electrical impulses from the retina to the primary visual centers of the brain via the optic nerve. Although retinal ganglion cells are essential for vision, how they form and why they die in retinal disease is poorly understood. We have discovered that a genetic network of transcription factors directs the formation of retinal ganglion cells. A factor called Math5 is required for making progenitor cells competent to advance to a retinal ganglion cell fate while two factors called Brn3b and Isl1 are necessary to mediate Math5’s function for overt retinal ganglion cell differentiation. We have placed Math5 at the highest hierarchal level and Brn3b and Isl1 at the next level in the genetic regulatory network responsible for retinal ganglion cell formation. Our current investigations are aimed at elaborating the network using a combination of genetic and genomic approaches. The predictive power of the network has allowed us to create adult mouse genetic models for optic nerve degeneration and visual dysfunction.
In a second project, we are investigating the role of the muscle-specific transcription factor myogenin during skeletal muscle development, growth, and repair. We have developed genetically engineered mouse models in which we can remove the myogenin gene at different times during embryonic, fetal and postnatal development. Our studies show that myogenin is essential for initial skeletal muscle differentiation in the embryo and that it also has functions in muscle growth and repair. Our current investigations are aimed at understanding how myogenin exerts its critical functions. In particular, we are addressing the biochemical basis for why myogenin is able to activate specific steps in skeletal muscle differentiation while closely related transcription factors activate other steps.
Cell layers of a mature mouse retina:
Left panel shows the layers of the retina labeled with fluorescent probes. Right panel shows a schematic representation. Retinal ganglion cells are found within the ganglion cell layer (GCL). Intermediate neurons are found within the inner nuclear layer (INL), and rod and cone photoreceptor cells are found within the outer nuclear layer (ONL). IPL and OPL are inner plexiform and outer plexiform layers where axons are found. PE is pigmented epithelium.
Program in Genes and Development
Office: MDA BSRB S9.8336C (Unit 1000)
Ph.D. - University of Illinois - 1973