Advisor(s)
Lynn Dobrunz
Committee Member(s)
Craig Powell
Farah Lubin
Scott Wilson
Summer Thyme
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
9-11-2025
Abstract
Polyubiquitination is a post-translational modification which often results in degradation of the ubiquitin-tagged protein. E3 ubiquitin ligases are multi-subunit protein complexes that assist in this ubiquitination process. Multiple genes that play a role in ubiquitination are implicated in autism spectrum disorder, a highly heterogeneous neurodevelopmental disorder. CULLIN3 (CUL3), a scaffolding protein part of the E3 ubiquitin ligase complex, is the product of a high-risk autism gene implicated across multiple large scale sequencing studies of autism patients. Additionally, CUL3 haploinsufficiency is associated with a syndromic disorder called NEDAUS (Neurodevelopmental disorder with or without autism or seizures) characterized by intellectual disability (ID), developmental delay, speech delay and motor impairments. Recent studies investigating heterozygous Cul3 deletion, in constitutive and conditional rodent knockout models, as well as iPSC-derived neuronal cells implicate CUL3 in neuronal migration, apoptosis, synaptic transmission, brain size, and ASD-relevant behavioral phenotypes. Given that Cul3 homozygotes are embryonically lethal, we sought to understand the function of Cul3 in an in vivo homozygous model in predominantly forebrain excitatory neurons at a later point in neurodevelopment. To achieve this, we crossed mice expressing Cre- recombinase under the control of CaMKIIa promoter and floxed Cul3 mice that resulted in viable homozygotes. Using this model, we studied the effects of delayed postnatal iii deletion of Cul3 on ASD-relevant behaviors. In this study, we show that delayed postnatal deletion of Cul3 in predominantly forebrain excitatory neurons results in behavioral abnormalities across multiple domains. Conditional Cul3 homozygotes exhibit repetitive jumping, reduced marble burying, increased locomotor activity, impaired motor coordination, and increased hindlimb clasping; these behavioral findings imply a change in brain function. Future work will focus on uncovering the molecular and cellular mechanisms by which Cul3 regulates neural circuit function in the adult brain.
ProQuest ID
Recommended Citation
Sekar, Prathibha, "Understanding The Functional Consequence Of Cul3 Deletion In The Mammalian Brain" (2025). All ETDs from UAB. 7441.
https://digitalcommons.library.uab.edu/etd-collection/7441
