Eylem Seç
Notch Signaling in the Adult Olfactory Epithelium: Roles in Stem Cell Quiescence, Lineage Specification, and Neuronal Maturation
Başlık:
Notch Signaling in the Adult Olfactory Epithelium: Roles in Stem Cell Quiescence, Lineage Specification, and Neuronal Maturation
Yazar:
Herrick, Daniel B., author.
ISBN:
9780438031074
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (175 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: James E. Schwob Committee members: John Castellot; Tom Gridley; Charlotte Kuperwasser.
Özet:
The adult olfactory epithelium (OE) has the remarkable capacity to regenerate fully both neurosensory and non-neuronal cell types after severe epithelial injury. Life-long persistence of two stem cell populations brings about OE regeneration when damaged: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells (GBCs). Both populations regenerate all cell types of the OE after injury, but the mechanisms underlying HBC activation, neuronal vs. non-neuronal lineage commitment after recruitment of the stem cell pools, and the role of Notch in neuronal maturation all remain unknown.
In the first set of experiments (Chapter 3), I first provide a thorough immunohistochemical characterization of Notch in the adult OE and a thorough analysis of the differential Notch gene regulation in the setting of various lesion types. I first performed cell-population specific ablations using either surgical olfactory bulbectomy (OBX) to selectively deplete the mature neuron layer or a transgenic mouse to selectively deplete Sustentacular support cells using Sus-cell specific expression of diphtheria toxin subunit A. We show for the first time that Sus cell ablation is sufficient for HBC activation to multipotency. Through genetic manipulation of Notch receptors, the data also suggest that Notch signaling contributes to maintenance of HBC quiescence through a positive regulation of p63, the master regulator of HBC quiescence. Additionally, Notch1 plays a critical role in maintaining quiescence in the presence of severe neural injury or increased neurogenesis. Importantly, this study reveals that Notch1 and Notch2 do not play redundant roles in HBCs and the impact of Notch-ON on maintaining p63 levels is not Notch receptor dose-dependent.
In Chapter 4, I show that once HBCs are activated, Notch signaling determines progenitor cell fate. We utilized both retroviral transduction and mouse lines that permit conditional cell-specific genetic manipulation as well as the tracing of progeny to study the role of canonical vs. non-canonical Notch signaling in the determination of neuronal vs. non-neuronal lineages in the regenerating adult OE. Excision of either Notch1 or Notch2 genes alone in HBCs did not alter progenitor fate during recovery from epithelial injury, while conditional knockout of both Notch1 and Notch2 together, retroviral transduction of progenitors with a dominant-negative form of MAML, or excision of the downstream cofactor RBPJ caused progeny to adopt a neuronal fate exclusively. Conversely, we show that overexpressing the Notch1-intracellular domain (N1ICD) either genetically or by transduction blocks neuronal differentiation completely. However, N1ICD overexpression requires both alleles of the canonical cofactor RBPJ to specify downstream lineage. Taken together, our results suggest that canonical RBPJ-dependent Notch signaling through redundant Notch1 and Notch2 receptors is both necessary and sufficient for determining neuronal vs. non-neuronal differentiation in the regenerating adult OE.
Finally, in Chapter 5, using drivers specific for neuronally committed progenitors (Ascl1 and Neurog1), I determined the role of Notch signaling in neural progenitors after lineage had been determined. In the uninjured epithelium, a low level of neurogenesis occurs throughout adult life. In neuronally committed progenitors, RBPJ is required for neuronal maturation. In fact, RBPJ haploinsufficiency is sufficient to prevent neuronal maturation. However, upon loss of mature neurons by OBX or loss of all differentiated cells by chemical lesion, RBPJ is no longer required for neuronal maturation.
Notlar:
School code: 0845
Konu Başlığı:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678630.1) | 678630-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.