Author ORCID Identifier

https://orcid.org/0000-0003-3163-739X

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Biochemistry

First Advisor

Dr. Emilia Galperin

Abstract

The canonical ERK1/2 signaling cascade regulates cellular functions critical in vertebrate embryonic development such as proliferation, apoptosis, differentiation, and migration. Thus, its signals are controlled by a variety of mechanisms. Scaffold proteins are considered central to the mechanisms regulating the transmission of the ERK1/2 signals. Yet, their functions in development nor the molecular mechanisms by which they exert their control are not well understood.

This study focuses on the essential regulator of ERK1/2 signals during development – the scaffold protein Shoc2. Loss of Shoc2 leads to early embryonic lethality in mice and zebrafish. Germline mutations in the shoc2 gene result in the developmental disorder ‘Noonan syndrome like with loose anagen hair’ (NSLH) with a spectrum of developmental abnormalities, including craniofacial dysmorphism, cardiac defects, growth delays, and neurologic issues. The loss of Shoc2 and the shoc2 NSLH-causing mutations affect the tissues of neural crest origin.

This dissertation addressed the role of Shoc2 in the development of neural crest cell-derived tissues. Studies here established that the loss of Shoc2 significantly alters the expression of transcription factors regulating the specification, migration, and differentiation of neural crest cells. Comparative transcriptome analysis of neural crest-derived cells from shoc2 CRISPR/Cas9 mutant larvae shows that Shoc2-mediated signals regulate gene programs at several levels. This study demonstrates that the loss of Shoc2 affected the expression of extracellular matrix (ECM) proteins and ECM regulators. Together, these results demonstrate that Shoc2 is an essential regulator of neural crest development and indicates that disbalance in the turnover of the ECM may lead to the abnormalities found in NSLH patients.

The work presented here also identifies the requirement of Shoc2-mediated signals for the development of lymphatic vasculature. Using a novel Shoc2 model (shoc2 c.1546 G>A) we determined that critical lymphatic vessels such as the thoracic duct and its derivative (the parachordal line) are absent in Shoc2 null larvae. These data suggest that the expression of Shoc2 is essential for lymphangiogenesis.

In summary, studies presented in this dissertation make significant advances in delineating the role of Shoc2 during the development of several diverse tissues. These findings will facilitate future work to explain the etiology of NSLH.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.333

Funding Information

This study was supported by the National Institute of General Medical Sciences to Emilia Galperin (no.: R35GM136295) Years 2020-2022


This study was supported by the National Institutes Health to Emilia Galperin. (1S10OD025033-01) Years: 2018-2019

Available for download on Saturday, August 10, 2024

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