Author ORCID Identifier

https://orcid.org/0000-0002-5501-2776

Date of Award

Spring 4-15-2026

Document Type

Thesis (Ph.D.)

Department or Program

Molecular and Systems Biology

First Advisor

Bryan Luikart

Second Advisor

Giovanni Bosco

Third Advisor

N/A

Abstract

Autism spectrum disorders (ASD) are genetically heterogeneous neurodevelopmental conditions that nevertheless converge on altered neuronal connectivity and circuit function. A central unresolved problem in the field is how diverse genetic perturbations, acting at different biological levels and developmental stages, give rise to shared neurodevelopmental outcomes. This dissertation addresses this problem by examining how gene function, subcellular signaling, and developmental context interact to shape neuronal morphology and circuit-relevant phenotypes.

Cell-autonomous mechanisms regulating neuronal morphology are examined through the ASD risk gene Phosphatase and Tensin Homolog (PTEN) in developing dentate gyrus granule neurons. Selective biasing of PTEN to defined intracellular compartments in vivo suggest that PTEN function is dictated by subcellular localization rather than overall protein abundance. Nuclear sequestration of PTEN produces neuronal hypertrophy and excessive dendritic branching resembling Pten loss, whereas enrichment of PTEN at dendritic extremities suppresses dendritic growth beyond wildtype levels. These findings support a model in which localized PTEN signaling contributes to the regulation of neuronal structure.

PTEN-dependent regulation of neuronal morphology is further examined in the context of developmental timing. Longitudinal 2-photon imaging of dendritic protrusions, manipulation of extrinsic growth factor signaling, and in vivo estimation of PTEN protein lifetime demonstrate that neuronal morphology is shaped by dynamic processes during postnatal development. Together, these results indicate that neuronal structure reflects the integration of localized signaling over time.

Systems-level developmental mechanisms contributing to ASD risk are examined through the gene Katanin Catalytic Subunit A1 Like 2 (KATNAL2). Loss of KATNAL2 disrupts radial glial-associated processes critical for brain development, including ependymal ciliary organization and cerebrospinal fluid dynamics, and is associated with ventriculomegaly and altered neuronal physiology in the absence of gross cortical malformation. Functional analysis of a patient-associated KATNAL2 variant supports a role for KATNAL2 in neurodevelopmental processes relevant to brain organization and function.

Collectively, these findings highlight that neurodevelopmental phenotypes can arise from mechanisms operating at multiple biological scales, including subcellular signaling within neurons and tissue-level developmental processes. This work provides an integrated framework for examining how spatial and temporal regulation of gene function contributes to neuronal development.

Comments

N/A

Original Citation

N/A

Download

Share

COinS