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Experimental and Theoretical Studies of Notch Signaling-Mediated Spatial Pattern


Lakhanpal, Amit (2014) Experimental and Theoretical Studies of Notch Signaling-Mediated Spatial Pattern. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RGPT-RS80.


Notch signaling acts in many diverse developmental spatial patterning processes. To better understand why this particular pathway is employed where it is and how downstream feedbacks interact with the signaling system to drive patterning, we have pursued three aims: (i) to quantitatively measure the Notch system's signal input/output (I/O) relationship in cell culture, (ii) to use the quantitative I/O relationship to computationally predict patterning outcomes of downstream feedbacks, and (iii) to reconstitute a Notch-mediated lateral induction feedback (in which Notch signaling upregulates the expression of Delta) in cell culture. The quantitative Notch I/O relationship revealed that in addition to the trans-activation between Notch and Delta on neighboring cells there is also a strong, mutual cis-inactivation between Notch and Delta on the same cell. This feature tends to amplify small differences between cells. Incorporating our improved understanding of the signaling system into simulations of different types of downstream feedbacks and boundary conditions lent us several insights into their function. The Notch system converts a shallow gradient of Delta expression into a sharp band of Notch signaling without any sort of feedback at all, in a system motivated by the Drosophila wing vein. It also improves the robustness of lateral inhibition patterning, where signal downregulates ligand expression, by removing the requirement for explicit cooperativity in the feedback and permitting an exceptionally simple mechanism for the pattern. When coupled to a downstream lateral induction feedback, the Notch system supports the propagation of a signaling front across a tissue to convert a large area from one state to another with only a local source of initial stimulation. It is also capable of converting a slowly-varying gradient in parameters into a sharp delineation between high- and low-ligand populations of cells, a pattern reminiscent of smooth muscle specification around artery walls. Finally, by implementing a version of the lateral induction feedback architecture modified with the addition of an autoregulatory positive feedback loop, we were able to generate cells that produce enough cis ligand when stimulated by trans ligand to themselves transmit signal to neighboring cells, which is the hallmark of lateral induction.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:developmental biology synthetic morphology notch delta
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Elowitz, Michael B.
Thesis Committee:
  • Sternberg, Paul W. (chair)
  • Elowitz, Michael B.
  • Hay, Bruce A.
  • Phillips, Robert B.
Defense Date:1 July 2013
Funding AgencyGrant Number
Fannie and John Hertz FoundationUNSPECIFIED
Record Number:CaltechTHESIS:10312013-102814054
Persistent URL:
Related URLs:
URLURL TypeDescription
http:/ adapted for ch.2 DOIArticle adapted for ch.3 adapted for ch.3
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8021
Deposited By: Amit Lakhanpal
Deposited On:21 Nov 2013 17:14
Last Modified:04 Oct 2019 00:03

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