Type
Text
Type
Dissertation
Advisor
Thomsen, Gerald H | Sirotkin, Howard | Takemaru, Ken-Ichi | Khokha, Mustafa.
Date
2015-12-01
Keywords
Neural development, PQBP1, Xenopus | Genetics
Department
Department of Genetics.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77631
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
The pqbp1 (polyglutamine tract-binding protein 1) gene has been associated with a number of developmental and neurodegenerative disorders, such as Huntington’s disease, spinocerebellar ataxia type 1, and a variety of X-linked intellectual disabilities grouped together under the umbrella term Renpenning Syndrome. Renpenning Syndrome is an X-linked recessive disorder involving intellectual disability, as well as physical features such as microcephaly, micropthalmia, lean build, short stature, and small testes. Work in the Thomsen Lab previously determined that a disruption in cellular levels of PQBP1 can impact crucial developmental processes such as gastrulation and neural tube closure. A reduction in PQBP1 levels was found to perturb the splicing regulation or transcription of two components of the FGF pathway (FGFR2 and FGF4), a critical developmental pathway. Specifically, changes were seen in the levels of the two FGFR2 transcripts. As these splice forms have different ligand binding affinities, this would be expected to alter the nature of FGF signaling, which performs an essential role in a variety of developmental processes. Several other critical signal transduction pathways - BMP, Activin, and Nodal - were not affected. This project is particularly focused on investigating the impact of modulating PQBP1 levels on neural function, since increasing our knowledge in this area has direct relevance to human disease phenotypes. I am using a well-established model organism for studying early development, the frog Xenopus. Knockdown of PQBP1 levels by splice morpholino demonstrated a severe eye phenotype as well as a reduction in the length of the anterior-posterior body axis. These phenotypes could be rescued by pqbp1 mRNA. Knock down of PQBP1 in this neuralized animal caps affected a variety of early and later neural markers. In situ hybridization experiments on whole embryos revealed similar impacts on neural markers, in addition to changes in the specific regions of marker expression. This work lends new insight into the aspects of early neural development that are impacted by PQBP1, and provides guidelines for further research into the developmental mechanisms underlying Renpenning syndrome and other pqbp1-related disorders. | The pqbp1 (polyglutamine tract-binding protein 1) gene has been associated with a number of developmental and neurodegenerative disorders, such as Huntington’s disease, spinocerebellar ataxia type 1, and a variety of X-linked intellectual disabilities grouped together under the umbrella term Renpenning Syndrome. Renpenning Syndrome is an X-linked recessive disorder involving intellectual disability, as well as physical features such as microcephaly, micropthalmia, lean build, short stature, and small testes. Work in the Thomsen Lab previously determined that a disruption in cellular levels of PQBP1 can impact crucial developmental processes such as gastrulation and neural tube closure. A reduction in PQBP1 levels was found to perturb the splicing regulation or transcription of two components of the FGF pathway (FGFR2 and FGF4), a critical developmental pathway. Specifically, changes were seen in the levels of the two FGFR2 transcripts. As these splice forms have different ligand binding affinities, this would be expected to alter the nature of FGF signaling, which performs an essential role in a variety of developmental processes. Several other critical signal transduction pathways - BMP, Activin, and Nodal - were not affected. This project is particularly focused on investigating the impact of modulating PQBP1 levels on neural function, since increasing our knowledge in this area has direct relevance to human disease phenotypes. I am using a well-established model organism for studying early development, the frog Xenopus. Knockdown of PQBP1 levels by splice morpholino demonstrated a severe eye phenotype as well as a reduction in the length of the anterior-posterior body axis. These phenotypes could be rescued by pqbp1 mRNA. Knock down of PQBP1 in this neuralized animal caps affected a variety of early and later neural markers. In situ hybridization experiments on whole embryos revealed similar impacts on neural markers, in addition to changes in the specific regions of marker expression. This work lends new insight into the aspects of early neural development that are impacted by PQBP1, and provides guidelines for further research into the developmental mechanisms underlying Renpenning syndrome and other pqbp1-related disorders. | 159 pages
Recommended Citation
Oomen-Hajagos, Jamina, "The Function of pqbp1, a Causative Gene for Renpenning Syndrome, During Early Neural Development in Xenopus" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 3426.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/3426