Many cell types must become polarized to function properly within a tissue or to generate distinct daughter cells. A quintessential example of this phenomenon is observed in the eggs of Caenorhabditis elegans. Shortly after fertilization, the C. elegans zygote undergoes a dramatic, stereotyped polarization that segregates polarity factors and cell fate determinants to the anterior and posterior ends of the egg. These asymmetries are essential for cellular differentiation and organismal development. Genetic analyses have demonstrated an essential role for the conserved Serine/Threonine kinase PAR-1 in this process. Specifically, loss of par-1 protein activity in the zygote results in symmetric distributin of normally asymmetric factors. In this proposal I will combine new technologies with classical techniques to analyze PAR-1 function in live embryos.
In Aim1, I will use optogenetic and Cas9 genome editing technologies to assign function to the different PAR-1 domains and test the role of PAR-1 asymmetry in patterning the zygote.
In Aim 2, I will conduct an unbiased chemical genetic screen to identify critical PAR-1 substrates. This work will uncover the molecular mechanisms used by PAR-1 to pattern the zygote and regulate cell and organismal polarity.

Public Health Relevance

The polarity kinase PAR-1 is a conserved regulator of cellular polarity from yeast to humans. The proposed work will answer critical outstanding questions surrounding PAR-1 function. Given the central role for PAR-1 in cellular polarity, this work will be broadly relevant to our understanding of cell biology in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM117814-01
Application #
9050199
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hoodbhoy, Tanya
Project Start
2016-05-15
Project End
2018-05-14
Budget Start
2016-05-15
Budget End
2017-05-14
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Paix, Alexandre; Folkmann, Andrew; Goldman, Daniel H et al. (2017) Precision genome editing using synthesis-dependent repair of Cas9-induced DNA breaks. Proc Natl Acad Sci U S A 114:E10745-E10754