The effects of genetic and environmental perturbations on craniofacial development
Abstract/Contents
- Abstract
- Formation of craniofacial structures is a delicate developmental process that is disrupted in many disease states. These disease states can occur due to genetic anomalies within a developing embryo or environmental irregularities in utero during gestation. Frequently, craniofacial developmental disorders are caused by defects in a particular population of transient, migratory stem cells called neural crest cells. In my Dissertation research, I have endeavored to elucidate the molecular and cellular mechanisms underlying specific genetic disorders and exposure to specific teratogens, with a focus on the fascinating cell type that is the neural crest cell (NCC). To this end, I have studied craniofacial disorder Floating-Harbor Syndrome (FHS), which is caused by heterozygous truncating mutations in SRCAP, a gene encoding a chromatin remodeler that mediates incorporation of histone variant H2A.Z. I demonstrated that FHS-associated mutations result in loss of SRCAP nuclear localization, alter neural crest gene programs in human in vitro models and Xenopus laevis embryos, and cause craniofacial defects. These defects are mediated by one of two H2A.Z subtypes, H2A.Z.2, whose knockdown mimics and whose overexpression rescues the FHS phenotype. Selective rescue by H2A.Z.2 is conferred by one of the three amino acid differences that evolved between the H2A.Z subtypes, S38/T38. I further showed that H2A.Z.2 preferentially occupies AT-rich enhancers, while H2A.Z.1 broadly binds regulatory regions, with the highest enrichment at promoters. Genes associated with H2A.Z.2-enriched enhancers are sensitized to heterozygous SRCAP truncations. Altogether, these results illuminate the mechanism underlying a human syndrome and uncover selective functions of H2A.Z subtypes during development. In addition, I have studied how Zika virus (ZIKV) infection during pregnancy, which is linked to microcephaly, can affect neural crest cell in vitro. In addition to giving rise to most cranial bones, NCCs exert paracrine effects on the developing brain. I reported that NCCs are productively infected by ZIKV, but not by the related dengue virus. These ZIKV-infected NCCs undergo limited apoptosis but secrete cytokines that promote death and drive aberrant differentiation of neural progenitor cultures. Addition of two such cytokines, LIF or VEGF, at levels comparable to those secreted by ZIKV-infected NCCs is sufficient to recapitulate premature neuronal differentiation and apoptotic death of neural progenitors. My results suggest that NCC infection by ZIKV may contribute to associated embryopathies through signaling crosstalk between developing face and brain structures.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Greenberg, Rachel Segal | |
|---|---|---|
| Degree supervisor | Wysocka, Joanna, Ph. D | |
| Thesis advisor | Wysocka, Joanna, Ph. D | |
| Thesis advisor | Beachy, Philip Arden | |
| Thesis advisor | Cimprich, Karlene | |
| Thesis advisor | Kingsley, David M. (David Mark) | |
| Thesis advisor | Sherlock, Gavin | |
| Degree committee member | Beachy, Philip Arden | |
| Degree committee member | Cimprich, Karlene | |
| Degree committee member | Kingsley, David M. (David Mark) | |
| Degree committee member | Sherlock, Gavin | |
| Associated with | Stanford University, Department of Developmental Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Rachel Segal Greenberg. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Rachel Segal Greenberg
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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