The Nrg Growth Factors and Their Receptor ErbB4 in the Developing Brain: Delineation of Nrg3 Expression and Neuritogenesis

Abstract

The developing brain is a highly dynamic structure, making it repeatedly vulnerable to possible developmental abnormalities that can endure into adulthood. The neuregulin (Nrg) family of growth factors (Nrg1-4) and their receptor, ErbB4, have been linked to mental illnesses considered to emerge as a result of abnormal neural development, such as schizophrenia, bipolar disorder, and depression. In the normal central nervous system (CNS), Nrg-ErbB ligand- receptor pairs regulate several cellular functions integral to neural development, including the enhancement of neurite extension and roles in polarity-driven events such as neuronal migration and the establishment of radial glial morphology. Due to the roles of Nrg-ErbB pairs in the healthy and malignant brain, the aims of this thesis were to address fundamental gaps in knowledge and to expand on the roles of the Nrgs and ErbB4 in neural development. Towards these goals, we 1) characterized the spatiotemporal localization of Nrg3, an understudied Nrg, in the rat brain, 2) defined and characterized the effects of Nrgs1-3 and ErbB4 in neurite outgrowth of GABAergic interneurons, and 3) studied the potential role of Nrg-ErbB4 signaling in neuronal polarization through its interaction with the Par polarity complex. The results from this thesis revealed that the Nrgs and ErbB4 play important roles in the development of the CNS, specifically in the differentiation of GABAergic interneurons. Nrg3 was found to be the most widely expressed Nrg in CNS neurons, including GABAergic interneurons, and likely plays non- overlapping functional roles with the other Nrgs. Our studies also revealed that Nrgs1-3 do play redundant roles in neurite development of early GABAergic interneurons by increasing the number of neurites and dramatically enhancing neurite length, including axonal elongation. These effects were driven by the activation of ErbB4. Lastly, using biochemical and immunocytochemical techniques, we uncovered a novel Nrg-dependent association of ErbB4 with members of the Par polarity complex (Par6, Par3, aPKC, and Cdc42), a group of proteins important for radial glial morphology, neuronal migration, and axonal specification. Collectively, the findings of this thesis highlight biological processes of the Nrgs and ErbB4 in the developing CNS, including roles in neuronal differentiation. In addition, these findings may contribute to the development of promising therapies addressing ErbB4-driven psychiatric disorders, such as depression, bipolar disorder, and schizophrenia.