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Presenilin Function in Mouse Lens De...

Azimi, Mina.

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Presenilin Function in Mouse Lens Development.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Presenilin Function in Mouse Lens Development./
Author:	Azimi, Mina.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	141 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
Subject:	Biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10936713
ISBN:	9780438929562

Presenilin Function in Mouse Lens Development.
Azimi, Mina.

Presenilin Function in Mouse Lens Development. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 141 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--University of California, Davis, 2018.

This item must not be sold to any third party vendors.

The highly conserved Notch signaling pathway functions in the development of multiple tissues in the metazoan body, including the ocular lens. Canonical Notch signals are required for normal lens cell proliferation, secondary fibergenesis, and transition zone maintenance, with most pathway mutants exhibiting microphthalmia. A critical component of this pathway is Presenilin (Psen1 and Psen2 in mice). Psens are polytopic transmembrane proteins that serve as the catalytic subunit of γ-secretase, the protease complex responsible for the final cleavage of the Notch receptor that generates the Notch intracellular domain (NICD) fragment necessary for signal transmission. However, Psens have a multitude of substrates in addition to the Notch receptor, likely to make the loss of Psen1 and Psen2 genes in the mouse lens more catastrophic than loss of canonical Notch signaling. Indeed, the data presented in Chapter 2 reveals that, although consistent with previously reported phenotypes for other Notch pathway mutants such as Notch2 and Rbpj, loss of Psens during lens development leads to a greater loss of AEL marker expression and more defects in tissue maintenance, ultimately resulting in postnatal aphakia. Interestingly, these phenotypes are more similar to those observed in lens mutants lacking the Notch ligand Jagged1 (Jag1), and suggest that both Psens and Jag1 must have Notch-independent roles in the forming mouse lens. Furthermore, our genetic interaction data between Psen1 and Jag1 led us to explore these components more closely in the developing lens. Thus, the work presented in Chapter 3 focuses on the potential for Psens and Jag1 to interact at the protein level by testing for Psen-mediated cleavage of this Notch ligand. We first demonstrate in vivo presence of Jag1 isoforms having molecular weights that correspond to a process of sequential cleavages, similar to what is observed in Notch receptor activation. Like NICD, we show that the intracellular domain of Jag1, J1-ICD, has nuclear expression and is able to alter gene expression in B3 cells, suggesting that ligand-ICDs may possess intrinsic signaling capabilities.

ISBN: 9780438929562Subjects--Topical Terms:

522710
Biology.

Presenilin Function in Mouse Lens Development.
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520 $a The highly conserved Notch signaling pathway functions in the development of multiple tissues in the metazoan body, including the ocular lens. Canonical Notch signals are required for normal lens cell proliferation, secondary fibergenesis, and transition zone maintenance, with most pathway mutants exhibiting microphthalmia. A critical component of this pathway is Presenilin (Psen1 and Psen2 in mice). Psens are polytopic transmembrane proteins that serve as the catalytic subunit of γ-secretase, the protease complex responsible for the final cleavage of the Notch receptor that generates the Notch intracellular domain (NICD) fragment necessary for signal transmission. However, Psens have a multitude of substrates in addition to the Notch receptor, likely to make the loss of Psen1 and Psen2 genes in the mouse lens more catastrophic than loss of canonical Notch signaling. Indeed, the data presented in Chapter 2 reveals that, although consistent with previously reported phenotypes for other Notch pathway mutants such as Notch2 and Rbpj, loss of Psens during lens development leads to a greater loss of AEL marker expression and more defects in tissue maintenance, ultimately resulting in postnatal aphakia. Interestingly, these phenotypes are more similar to those observed in lens mutants lacking the Notch ligand Jagged1 (Jag1), and suggest that both Psens and Jag1 must have Notch-independent roles in the forming mouse lens. Furthermore, our genetic interaction data between Psen1 and Jag1 led us to explore these components more closely in the developing lens. Thus, the work presented in Chapter 3 focuses on the potential for Psens and Jag1 to interact at the protein level by testing for Psen-mediated cleavage of this Notch ligand. We first demonstrate in vivo presence of Jag1 isoforms having molecular weights that correspond to a process of sequential cleavages, similar to what is observed in Notch receptor activation. Like NICD, we show that the intracellular domain of Jag1, J1-ICD, has nuclear expression and is able to alter gene expression in B3 cells, suggesting that ligand-ICDs may possess intrinsic signaling capabilities.
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