Regulation of Temporal and Spatial Organization of Newborn GnRH Neurons by IGF Signaling

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How newborn neurons are organized into the right locations with the right timing to form functional circuits is a fundamental question in developmental neurobiology. An attractive model system in which to address this question is the Gonadotropin-releasing hormone (GnRH) neuronal system. GnRH neurons are master regulators of the reproductive system. They secrete GnRH peptides to initiate reproductive activity. Abnormal development of GnRH neurons can lead to reproductive disorders. Although significant advances have been made in understanding the central importance of GnRH neurons in reproduction, very little is known about where the GnRH progenitor (i.e., undifferentiated) cells are located in the developing nervous system and how they are instructed to become GnRH neurons. This project fills this gap in our knowledge. The anticipated results will provide new knowledge on how insulin-like growth factor (IGF) signaling, a major embryonic growth-promoting pathway, regulates GnRH neuronal development. The knowledge gained from this project may have applications in the aquaculture industry and will help understand the etiology of reproductive disorders. This project provides training opportunities for high school, undergraduate, and graduate students, and postdoctoral fellows. The students participate in all aspects of this cutting-edge research project. In collaboration with the University of Michigan Museum of Natural History, the project also includes the development of a summer camp curriculum in neurobiology, entitled "Shining Neurons in the Brain!", for K-12 students. This and other outreach activities make this NSF-funded research accessible to the public. An attractive model system in which to address the question of how newborn neurons are organized into the right locations with the right timing to form functional circuits is the GnRH neuronal system. GnRH neurons emerge from the nasal/olfactory placode in early embryos and undertake a long-distance migration from the olfactory region to the preoptic area and hypothalamus. The embryonic origin(s) of GnRH progenitor cells is still under debate. Little is known about how these progenitor cells are specified to give rise to GnRH neurons. Most vertebrate species have a second GnRH gene that is expressed in the midbrain. Much less is known about the GnRH2 neuron development and regulation. This project tests the hypothesis that the two types of GnRH neurons originate from the cranial neural crest- and/or optical placode-derived progenitor cells and that IGF signaling regulates the emergence of GnRH neurons at the right time and location by controlling the proliferation, migration, and/or survival of their progenitor cells. Perturbation of IGF signaling in a critical time window during early embryogenesis alters the temporal and spatial organization of the newborn GnRH neurons, which, in turn, affects reproductive function later in life. Aim 1 investigates the embryonic origins of GnRH neurons; Aim 2 determines whether IGF signaling regulates the emergence of the GnRH neurons by controlling migration, proliferation, and/or survival of their progenitor cells, and Aim 3 determines the long-term reproductive consequences of this regulation.