Interactions between cells influence many critical aspects of embryonic development. The broad goal of this proposal is to determine how cell interactions determine the shape and organization of cells, tissues, and organs during embryogenesis. Using the nematode C. elegans as an in vivo model where genetic analysis and live imaging can be combined, we have developed several simple experimental systems to investigate how cell interactions regulate conserved morphogenetic events as tissues and organs develop. In one project, we investigate how cell contacts induce apicobasal polarity in early embryonic cells. We recently showed that the adhesion protein E-cadherin induces polarity by recruiting the symmetry-breaking RhoGAP PAC-1 to cell contact sites, and also discovered that an unidentified redundant pathway contributes to polarization. We will extend these findings by determining how E-cadherin accumulates at cell contacts, investigating how the E-cadherin interacting protein ?-catenin recruits PAC-1, and identifying components of the redundant pathway that polarizes cells independently of E-cadherin. In a second project, we investigate how PAR polarity proteins regulate the formation of epithelial cell junctions and tubes. We showed previously that PAR-6 is required for the maturation of adherens junctions. To determine how it does so, we will clone and characterize mutations, which we identified in a genetic interaction screen, that affect junction integrity. Separately, we will determine how PAR proteins and the exocyst complex recognize lumenal domains and direct vesicle trafficking to these sites to extend intracellular tubes. In a third project, we investigate the mechanisms of a novel form of cellular morphogenesis we discovered - a cannibalistic event that occurs when endodermal cells actively bite off and digest large lobes extended by primordial germ cells (PGCs). Such a form of morphogenesis is likely to have been overlooked in other systems, and we hypothesize that it is critical for germ cell development. We found that the Rho GTPase Rac induces actin to accumulate at the base of PGC lobes and is required for the scission of these structures by endodermal cells. We will determine how Rac and actin function in lobe scission, and we will characterize several additional genes, which we identified in a genetic screen, that are essential for lobe scission. Together, our findings will reveal new, basic insights into how cells, tissues, and organs change shape and organize into functional units during development, and will provide a foundation for understanding the molecular basis of diseases characterized by defective cell-cell interactions, such as cancer.

Public Health Relevance

Physical interactions between cells influence many important aspects of embryo development. This proposal uses the nematode embryo as an experimentally accessible model to determine how cellular interactions regulate the shape and organization of tissues and organs. Our findings will provide insights into how cell interactions contribute to human embryo development, and how defective cellular interactions can contribute to birth defects and diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118081-02
Application #
9260908
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Hoodbhoy, Tanya
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Zilberman, Yuliya; Abrams, Joshua; Anderson, Dorian C et al. (2017) Cdc42 regulates junctional actin but not cell polarization in the Caenorhabditis elegans epidermis. J Cell Biol 216:3729-3744
Abdu, Yusuff; Maniscalco, Chelsea; Heddleston, John M et al. (2016) Developmentally programmed germ cell remodelling by endodermal cell cannibalism. Nat Cell Biol 18:1302-1310