| dc.identifier.uri | http://hdl.handle.net/11401/78896 | |
| dc.type | Text | |
| dcterms.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. | |
| dcterms.contributor | Committee members: Shelly, Maya; Halegoua, Simon; Walss-Bass, Consuelo | |
| dcterms.contributor | Advisors: Talmage, David; Role, Lorna | |
| dcterms.creator | Jone, Alice | |
| dcterms.dateAccepted | 2019-12-06T17:27:13Z | |
| dcterms.dateSubmitted | 2019-12-06T17:27:13Z | |
| dcterms.description | Department of Neurobiology and Behavior | |
| dcterms.description | Dissertation | |
| dcterms.extent | 93 pages | |
| dcterms.format | application/pdf | |
| dcterms.issued | 2019-01-01 | |
| dcterms.provenance | Submitted by Jason Torre (fjason.torre@stonybrook.edu) on 2019-12-06T17:27:13Z
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Jone_grad.sunysb_0771E_14322.pdf: 3919170 bytes, checksum: 0810a575ee7ba98116c334af10f0067e (MD5) | |
| dcterms.provenance | Made available in DSpace on 2019-12-06T17:27:13Z (GMT). No. of bitstreams: 1
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Previous issue date: 2019 | |
| dcterms.title | Neuregulin 1 Nuclear Signaling is Important for Postnatal Hippocampal Neurogenesis and Neuronal Development | |
