My students and I have been exploring various aspects of brain development that has resulted in several exciting findings. First, in cooperation with David Rapaport, PhD, Linda Erkman, PhD, and Jeff M. Rosenfield, MD, at U.C. San Diego, we have recently published our findings on the role that a new gene product, brain 3.2 (Brn 3.2), plays in establishing the early sensory pathways in the brain of all mammals. Published in the journal Neuron, we described that Brn 3.2 controls the migration of axons from their tissues of origin to their sites of termination within the rest of the central nervous system. Failure of this transcription factor to express itself results in the creation of numerous targeting errors within the developing fetal brain that ultimately results in the loss of these cells. In the developing retina, for example, we showed that deletion of the Brn 3.2 gene resulted in the loss of approximately 93% of the cells that normally make connections with the rest of the brain. Further work to determine the genes that are downstream of Brn 3.2 are currently ongoing and have implicated abLIM (a human actin-binding zinc-finger protein gene). Knowledge of the sequence of genes that form sensory structures within the brain hold great promise for repairing damage that has occurred in the brains of humans, and opens up the possibility of stem cell therapy towards this end.
The second major focus of my laboratory involves the recent discovery of the role that a newly discovered fibroblast growth factor 15 (FGF-15) plays in the development of retinal ganglion cells. Retinal ganglion cells are the cells that transmit light information from the eye to the rest of the central nervous system. While on sabbatical in the laboratory of Dr. Tom Reh, University of Washington, Seattle, we discovered that FGF-15 fates stem cells to become retinal ganglion cells. This exciting finding using tissue culture techniques has led to the funding of a large grant from the National Medical Testbed designed to determine the ability of stem cells to from new ganglion cells in the retina of adult mice. This work has revealed that FGF-15 is expressed very early in development and inhibited by several developmental processes that occur after this cell class in formed. We are currently exploring the early expression of receptors for FGF-15 and more importantly, the ability of FGF-15 treated stem cells to create new retinal ganglion cells and establish connections with the rest of the central nervous system in adult animals. I have recently been invited to present this work in Sydney Australia in August at the International Meeting for Visual Neuroscience.
The third major focus of my laboratory has been a series of unique and very exciting investigations that are exploring the role of neural innervation of the cervix. This work is a joint project between my lab and that of Dr. Steve Yellon, Center for Perinatal Biology, LLU. We have recently presented data at the annual Academy of Neurology meeting in Philadelphia that the cervix essentially remains without innervation throughout most of pregnancy and after parturition. The exception is a small window of time associated with the day prior to the onset of birth. How and why the cervix undergoes such a phenomenal increase in innervation in a short period of time is currently unknown. This ingrowth is correlated with cervical ripening and associated with changes in neutrophils and macrophages that Dr. Yellon and colleagues have previously reported. We are currently exploring the hypothesis that the nervous system may initiate a series of events that leads to birth. If correct, this would open several exciting and new ways to treat preterm labor. The presentation in Philadelphia was performed by Laura S. Kirby, a senior high school student, who did the actual work on this project. Laura was awarded the Neuroscience Research Prize by the Academy of Neurology for this work at their annual meeting in Philadelphia.
The fourth project involves work that was funded by a grant from the Swedish government to explore the role of the nervous system on bone development. This work has observed that one or more factors released by developing neurons has a pronounced effect on increasing osteoblast proliferation. My student, Colleen Moran, and I, and Dr. Tom Linkhart are currently exploring the potential neurotrophic factors that may stimulate osteoblast proliferation. This work may potentially open new avenues for the treatment of bone diseases that will use growth factors commonly associated with brain development but rarely thought of for bone growth.
Although each of these research directions is uniquely different, they all fall under the general category of brain development. Many of these projects have already substantially increased our understanding of the mechanisms by which the brain grows and develops. Several offer the promise for treating diseases that are at present only managed at a rudimentary level.