{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Neuregulin 1 Nuclear Signaling is Important for Postnatal Hippocampal Neurogenesis and Neuronal Development","metadata":[{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/78896"},{"label":"dcterms.abstract","value":"The Neuregulin 1 (Nrg1) gene encodes a family of versatile signaling proteins\nextensively involved in neural development and synaptic plasticity. One neuron-specific\nisoform, Type III Nrg1, is critical for neuronal survival, neural fate determination,\nreceptor trafficking, axon myelination, and synaptic transmission. Type III Nrg1\nundergoes regulated intramembranous proteolysis, resulting in cleavage by \u03b3-secretase\nbetween Cys320-Val321 and generating a carboxyl-terminal fragment that is capable of\ntranslocating to the nucleus, where it possesses strong transcriptional transactivation\nproperties. A single-nucleotide polymorphism associated with psychosis and\nschizophrenia in a human population in Costa Rica results in a Val321 to Leu321\nsubstitution (V321L). In vitro, the V321L mutation significantly impairs Type III Nrg1\nnuclear signaling and dendrite growth and branching. Therefore, I asked what happens\nto neuronal development in the context of hippocampal neurogenesis when the V321L\nmutation is introduced in vivo.\nFirst, I found that the proliferative neural progenitor population is significantly\ndecreased in the V321L mutant mouse dentate gyrus. However, the progenitors that\ncommitted to the neuronal fate were not decreased. This is accounted for in part by\nincreased survival of newborn cells as well as by accelerated neuronal fate\ncommitment. I showed through pulse-chase experiments that progenitors in the dentate\ngyrus exited the cell cycle at an increased rate, which resulted in directed postmitotic\nprogramming towards the neuronal fate, suggesting a role for Nrg1 nuclear signaling in\ncell cycle maintenance and suppression of neuronal fate in the postnatal dentate gyrus. Dentate granule cells birthed from accelerated fate commitment exhibited abnormal\ndendritogenesis. Doublecortin labeling and Golgi impregnation both showed decreased\ncomplexity in the dendritic arbors of immature and mature dentate granule cells in\nV321L mutants. Furthermore, V321L mutant mice display abnormal hippocampal\nneurogenesis-mediated behaviors. Preliminary c-Fos immunostaining revealed possible\nabnormal activation of neurons in the V321L dentate gyrus by stressful experiences.\nThus, my findings suggest that Nrg1 nuclear signaling is important for\nmaintaining proliferation in the dentate gyrus, directing postmitotic fate programming,\nand instructing dendrite development. Loss of Nrg1 nuclear signaling has functional\nconsequences for newborn neurons with respect to integration into the local circuitry, as\nwell as behaviorally for the animals."},{"label":"dcterms.contributor","value":"Committee members: Shelly, Maya; Halegoua, Simon; Walss-Bass, Consuelo"},{"label":"dcterms.creator","value":"Jone, Alice"},{"label":"dcterms.dateAccepted","value":"2019-12-06T17:27:13Z"},{"label":"dcterms.dateSubmitted","value":"2019-12-06T17:27:13Z"},{"label":"dcterms.description","value":"Dissertation"},{"label":"dcterms.extent","value":"93 pages"},{"label":"dcterms.format","value":"application/pdf"},{"label":"dcterms.issued","value":"2019-01-01"},{"label":"dcterms.provenance","value":"Submitted by Jason Torre (fjason.torre@stonybrook.edu) on 2019-12-06T17:27:13Z\nNo. of bitstreams: 1\nJone_grad.sunysb_0771E_14322.pdf: 3919170 bytes, checksum: 0810a575ee7ba98116c334af10f0067e (MD5)"},{"label":"dcterms.title","value":"Neuregulin 1 Nuclear Signaling is Important for Postnatal Hippocampal Neurogenesis and Neuronal Development"},{"label":"dc.type","value":"Text"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/15%2F72%2F53%2F157253538309664620273451246372161835593/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/15%2F72%2F53%2F157253538309664620273451246372161835593","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}