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New Capabilities of the Notch Signaling Pathway


Nandagopal, Nagarajan (2018) New Capabilities of the Notch Signaling Pathway. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z98050TB.


Animal cells use a conserved repertoire of signaling pathways to exchange information during and after development. The constituent molecules of these pathways and their individual interactions are now well-characterized. However, it is becoming clear that pathways often possess unexpected signal-processing capabilities, which are typically collective, systems-level, features. Recent work shows that these capabilities are best investigated using quantitative, single-cell, dynamic analyses of pathway behavior. Here, we used this approach to study Notch signaling pathway, which is widely utilized for juxtacrine signaling during the development and maintenance of most tissues. Our work reveals two new capabilities of this pathway. First, the receptor Notch1 is capable of discriminating between two similar ligands, Dll1 and Dll4, and can use this ability to enact ligand-specific developmental programs. To enable this, the pathway encodes ligand identity in the dynamics of Notch1 signaling, and later decodes it for controlling gene expression. We show that dynamic encoding by Dll1 and Dll4 results from different requirements for ligand-receptor clustering during activation. Second, the pathway is capable of cell-autonomous signaling (cis-activation). This mode of signaling is general to multiple ligand-receptor combinations, and possesses many attributes of intercellular signaling. We show that cis-activation occurs in natural stem-cell contexts, where it could be important for self-renewal and prevents premature differentiation. These new capabilities of this central signaling pathway have implications for understanding the role of Notch in development and homeostasis, diagnosing and treating its misregulation in disease, and controlling it for tissue engineering and regeneration.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Systems biology; Signaling pathways; Notch pathway; Information processing; Developmental biology
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Bioengineering
Awards:Everhart Distinguished Graduate Student Lecturer Award, 2017.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Elowitz, Michael B.
Thesis Committee:
  • Goentoro, Lea A. (chair)
  • Bronner, Marianne E.
  • Phillips, Robert B.
  • Elowitz, Michael B.
Defense Date:2 October 2017
Record Number:CaltechTHESIS:12282017-140713708
Persistent URL:
Related URLs:
URLURL TypeDescription CentralPortions of this article were adapted for Chapter 1.
Nandagopal, Nagarajan0000-0002-0469-6549
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10620
Deposited By: Nagarajan Nandagopal
Deposited On:25 Jan 2018 22:14
Last Modified:04 Oct 2019 00:19

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