Office: Science Center #126
Lab: Science Center #129
Neuroscience and Stem Cell Biology
Undifferentiated embryonic stem cells (ESC) derived from early embryos can replicate indefinitely and differentiate in vitro to become a wide variety of specialized cell types such as bone, muscle, liver, or blood cells. Recent studies have shown that ESC can be induced to differentiate into functional transplantable neurons in vitro following exposure to Retinoic Acid. Subsequently, diverse protocols have been developed to selectively promote neuronal differentiation of ESC into specific neuronal subtypes such as Dopaminergic, GABAergic and Motor neurons. As part of this collective effort, my laboratory at the Dominican University of California is currently investigating the potential of cultured mouse ESC to differentiate into neuroendocrine cells.
Neuroendocrine cells are a set of specialized neurons located in the hypothalamus. Rather than forming synapses with other neurons, these cells release their product, neurohormones, into the blood circulation to act on their endocrine targets. Neuroendocrine hypothalamus consists of eight neuronal populations, each expressing a specific complement of neurohormones and receptors. They are important because they control most of our vital functions, including growth, reproduction, nutrition, sleep, stress responses and homeostasis via hormonal balance. Moreover, the neuroendocrine hypothalamus is susceptible to a variety of developmental diseases or syndromes such as Kallmann’s (congenital disorder associated with hypogonadism), Prader-Willi (a disorder associated with autism), and Rubenstein-Taybi (condition characterized by short stature and moderate to severe mental retardation). Although neuroendocrine cells are an important component of the regulation of homeostasis and behavior, very little is understood about the mechanisms that control their differentiation during embryogenesis.
The in vitro differentiation of ESC recapitulates a number of normal developmental processes that occur in mammalian embryos. Therefore, the success of this project on neuroendocrine differentiation of mouse ESC will provide a powerful in vitro model for further investigating the cellular and molecular mechanisms that control the birth of hypothalamic neuroendocrine cells in early embryonic development. The wide range of genetic manipulations that are possible in ESC allows a number of experiments to be performed that are otherwise difficult or impossible in either primary hypothalamic neuronal culture or immortalized neuroendocrine cell lines. This work in mouse ESC will ultimately provide a methodology for studying human ESC differentiation into neuroendocrine neurons, and thus serve as a means for preliminary biological and therapeutic investigations.
Another ongoing project in my laboratory at Dominican is the phenotyping of the GPR-4 transgenic rats that I helped generate while working at UCSF. The GPR-4 rat is a line of transgenic rats in which the activity of the neurons secreting Gonadotropin-Releasing Hormone (GnRH), the main hormone controlling reproduction, has been genetically altered. For the last two years, I have been mentoring a group of Dominican undergraduate students investigating reproductive and metabolic abnormalities in the GPR-4 rats in a collaborative project with UCSF. Our findings, which are the subject of several abstracts to be presented at National and International Meetings (the 20th NCUR Meeting, Asheville, NC, April 6-8; the 89th Meeting of the Endocrine Society, Boston, MA, June 24-27; and the 6th International Congress of Neuroendocrinology, Pittsburgh, PA, June 19-22) revealed that middle-aged female GPR-4 rats not only become prematurely infertile but they also become obese. Interestingly, these reproductive and metabolic abnormalities were specific to the female and were not observed in the males. Our findings indicate that the line of GPR-4 transgenic rats may represent an excellent animal model for the understanding the biology underlying metabolic disorders associated with reproductive aging in women following menopause. I am hoping to continue this research project in collaboration with the Buck Institute who has recently shown interest in hosting these rats.