Alice Jone

Type

Text

Type

Dissertation

Advisor

Committee members: Shelly, Maya; Halegoua, Simon; Walss-Bass, Consuelo | Advisors: Talmage, David; Role, Lorna

Date

2019-01-01

Keywords

Nuclear Signaling, Postnatal Hippocampal Neurogenesis

Department

Department of Neurobiology and Behavior

Source

This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.

Identifier

http://hdl.handle.net/11401/78896

Publisher

The Graduate School, Stony Brook University: Stony Brook, NY.

Format

application/pdf

Abstract

The Neuregulin 1 (Nrg1) gene encodes a family of versatile signaling proteins extensively involved in neural development and synaptic plasticity. One neuron-specific isoform, Type III Nrg1, is critical for neuronal survival, neural fate determination, receptor trafficking, axon myelination, and synaptic transmission. Type III Nrg1 undergoes regulated intramembranous proteolysis, resulting in cleavage by γ-secretase between Cys320-Val321 and generating a carboxyl-terminal fragment that is capable of translocating to the nucleus, where it possesses strong transcriptional transactivation properties. A single-nucleotide polymorphism associated with psychosis and schizophrenia in a human population in Costa Rica results in a Val321 to Leu321 substitution (V321L). In vitro, the V321L mutation significantly impairs Type III Nrg1 nuclear signaling and dendrite growth and branching. Therefore, I asked what happens to neuronal development in the context of hippocampal neurogenesis when the V321L mutation is introduced in vivo. First, I found that the proliferative neural progenitor population is significantly decreased in the V321L mutant mouse dentate gyrus. However, the progenitors that committed to the neuronal fate were not decreased. This is accounted for in part by increased survival of newborn cells as well as by accelerated neuronal fate commitment. I showed through pulse-chase experiments that progenitors in the dentate gyrus exited the cell cycle at an increased rate, which resulted in directed postmitotic programming towards the neuronal fate, suggesting a role for Nrg1 nuclear signaling in cell cycle maintenance and suppression of neuronal fate in the postnatal dentate gyrus. Dentate granule cells birthed from accelerated fate commitment exhibited abnormal dendritogenesis. Doublecortin labeling and Golgi impregnation both showed decreased complexity in the dendritic arbors of immature and mature dentate granule cells in V321L mutants. Furthermore, V321L mutant mice display abnormal hippocampal neurogenesis-mediated behaviors. Preliminary c-Fos immunostaining revealed possible abnormal activation of neurons in the V321L dentate gyrus by stressful experiences. Thus, my findings suggest that Nrg1 nuclear signaling is important for maintaining proliferation in the dentate gyrus, directing postmitotic fate programming, and instructing dendrite development. Loss of Nrg1 nuclear signaling has functional consequences for newborn neurons with respect to integration into the local circuitry, as well as behaviorally for the animals. | 93 pages

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