Differentiated cell types originate during development from precursor cells that have the potential to give rise to multiple cell types. Commitment to a cell fate depends on the external environment of the precursor cell and its intrinsic genetic program at any moment in time. My laboratory is investigating how gene expression programs are controlled when precursor cells differentiate into specific 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 genetically engineered mouse models to delineate how particular transcription factors work to program cellular differentiation. In one project, we identified the key transcription factors that regulate the differentiation of the ganglion cells of the 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 two transcription factors play critical roles in the formation of retinal ganglion cells. A factor called Math5 is required for making precursor cells competent to commit to a retinal ganglion cell fate while a second factor called Pou4f2/Brn3b is necessary for overt retinal ganglion cell differentiation and cell survival. We have placed Math5 and Pou4f2/Brn3b as central nodes in a gene 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. By taking advantage of our knowledge of retinal ganglion cell development, we are using genetic ablation approaches to generate a mouse model for optic nerve degeneration. This model should be valuable for studying the repair and regeneration of damaged retinas.

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 is likely to have 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 by which myogenin is able to activate specific steps in skeletal muscle differentiation while closely related transcription factors activate other steps.

As a useful and evolutionarily relevant model, we are investigating cellular differentiation in the sea urchin. Sea urchins are echinoderms, basal deuterostomes positioned along the evolutionary branch that gives rise to chordates. We have a long-term interest in the mechanisms controlling gene expression in the differentiation of the earliest cell types that arise from precursor cells immediately after fertilization, particularly ectoderm cell types. We have also begun a study on the evolutionary origin of photosensory systems in deuterostomes. Genes whose expression in the retina was dependent on Math5 were used to identify homologous genes from the sea urchin genome. Several genes encoding retinal-specific transcription factors were identified and their expression was shown to be in adult sea urchin tube feet – tissues containing neurons thought to be associated with sensory functions. The results suggest that sea urchin tube feet function as photoreceptors and that photoreception evolved in a novel way in sea urchins.

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.

Selected publications