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δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry

Cooper, Sharon Rose
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492457066344753

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Selective cell-to-cell adhesion is essential for normal development of the vertebrate brain, contributing to coordinated cell movements, regional partitioning and synapse formation. Members of the cadherin superfamily mediate calcium-dependent cell adhesion, and selective adhesion by various family members is thought to contribute to the development of neural circuitry. Members of the δ-protocadherin subfamily of cadherins are differentially expressed in the vertebrate nervous system and have been implicated in a range of neurodevelopmental disorders: schizophrenia, mental retardation, and epilepsy. However, little is known about how the δ-protocadherins contribute to the development of the nervous system, nor how this development is disrupted in the disease state. Here I focus on one member of the δ-protocadherin family, protocadherin-19 (pcdh19), since it has the clearest link to a neurodevelopmental disease, being the second most clinically relevant gene in epilepsy. Using pcdh19 transgenic zebrafish, we observed columnar modules of pcdh19-expresing cells in the optic tectum. In the absence of Pcdh19, the columnar organization is disrupted and visually guided behaviors are impaired. Furthermore, similar columns were observed in pcdh1a transgenic zebrafish, located both in the tectum and in other brain regions. This suggests protocadherin defined columns may be a theme of neural development. Our X-ray crystal structure of Pcdh19 reveals the adhesion interface for Pcdh19 and infers the molecular consequences of epilepsy causing mutations. We found several epilepsy causing mutations were located at the interface and disrupted adhesion, which further validated the interface and revealed a possible biochemical cause of Pcdh19 dysfunction. Furthermore, sequence alignments of other δ-protocadherins with Pcdh19 suggest that this interface may be relevant to the entire δ-protocadherin subfamily. We used the information gained about Pcdh19 to design PCDH19-FE mutations in the genome of zebrafish for comparing the circuitry of embryos with wild-type pcdh19, non-adhesive pcdh19 or without pcdh19. The combination of in vitro adhesion studies and in vivo brain imaging analysis provides a more comprehensive understanding of protocadherin-19 function, and suggests a broader role for the δ-protocadherin family in differential adhesion during brain development.
James Jontes (Advisor)
Marcos Sotomayor (Advisor)
Heithem El-Hodiri (Committee Member)
Sharon Amacher (Committee Member)
210 p.
Biochemistry; Biology; Biomedical Research; Biophysics; Cellular Biology; Developmental Biology; Molecular Biology; Neurosciences
epilepsy; EFMR; Pcdh19; protocadherins; cadherins; calcium binding; adhesion; neurons; neural circuitry; neural development; brain development; neuroscience; biophysics; structural biology; zebrafish; superior colliculus; optic tectum; TALEN

Recommended Citations

Citations

  • Cooper, S. R. (2017). δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492457066344753

    APA Style (7th edition)

  • Cooper, Sharon. δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry . 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492457066344753.

    MLA Style (8th edition)

  • Cooper, Sharon. "δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry ." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492457066344753

    Chicago Manual of Style (17th edition)

osu1492457066344753
883
© 2017, some rights reserved.Creative Commons License δ-Protocadherin Function: From Molecular Adhesion Properties to Brain Circuitry by Sharon Rose Cooper is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.