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Author ORCID Identifier
https://orcid.org/0000-0002-4132-7953
AccessType
Campus-Only Access for Five (5) Years
Document Type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Molecular and Cellular Biology
Year Degree Awarded
2023
Month Degree Awarded
September
First Advisor
ChangHui Pak
Second Advisor
Daniel Hebert
Third Advisor
Rolf Karlstrom
Fourth Advisor
Margaret Stratton
Subject Categories
Developmental Neuroscience
Abstract
Calcium/calmodulin-dependent serine protein kinase (CASK), a member of the membrane-associated guanylate kinase (MAGUK) family, is a multidomain scaffolding protein highly expressed throughout the mammalian brain and has been associated with a number of severe neurodevelopmental disorders (NDDs), including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, X-linked intellectual disabilities (IDs), and autism spectrum disorders (ASDs). Demonstrated in both invertebrate models and rodents, CASK can function in several distinct ways depending on its subcellular localization, protein environment, and the developmental time window of expression. CASK binding partners include the synaptic cell adhesion molecule neurexin-1 (NRXN1, also implicated in NDDs), voltage-gated calcium channels, the developmental transcription factor Tbr1 and adapter protein CINAP, and Mint1 and Veli, adapter proteins at the presynaptic active zone. Interestingly, heterozygous deletion of NRXN1 in human neurons derived from schizophrenia patient genetic background leads to a significant increase in CASK protein stability. While predominantly studied in invertebrates and mice, our preliminary understanding of human CASK function disagrees with other models and remains elusive. There is also a substantial lack of in vitro human CASK protein-protein interaction studies, preventing any cellular or developmental context of potential signaling mechanisms regulated by CASK. To provide better, more-informed care and novel therapies for patients with CASK loss-of-function (LOF) mutations, insights into the underlying molecular and cellular pathogenesis of CASK deficiencies must be pursued to unravel these underexplored but potentially insightful paths of discovery. Here, we discuss the molecular and cellular consequences and functional deficits of CASK-knockout (KO) human induced neural cells generated in an isogenic background using CRISPR/Cas9-engineering and stem-cell differentiation methods that mimic CASK deficiencies in patients, followed by our ongoing characterization of CASK binding partners and protein networks in our efforts to better inform CASK biology at the molecular level.
DOI
https://doi.org/10.7275/35957148
Recommended Citation
McSweeney, Danny B., "Investigating Signaling Mechanisms of Neuronal Maturation and Synapse Function Using Human Induced Neuronal Cells" (2023). Doctoral Dissertations. 2906.
https://doi.org/10.7275/35957148
https://scholarworks.umass.edu/dissertations_2/2906
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.