자료유형  

 학위논문

Control Number  

0017162862

International Standard Book Number  

9798382740706

Dewey Decimal Classification Number  

575

Main Entry-Personal Name  

Toolan, Kevin Patrick.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

142 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

General Note  

Advisor: Bielas, Stephanie;Camper, Sally Ann.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2024.

Summary, Etc.  

요약Over 100 genes have been implicated in the genetic etiology of autism spectrum disorder (ASD). Many high confidence ASD genes are involved in chromatin remodeling, histone modifications and DNA methylation. Among these is ASH1L (Absent, Small, Homeotic-Like 1), which catalyzes histone H3K36 methylation and has a role in activating transcription by counteracting Polycomb repression. Over 130 autistic individuals have heterozygous loss-of-function ASH1L variants, and population studies confirm it is a high-risk autism gene. Several studies report autism-like behaviors in Ash1l deficient mice and characterized aspects of the underlying neuropathophysiology. However, the underlying genetic aberrations caused by Ash1l loss-of-function are poorly understood in the context of cortical development. We used mice with a cre-inducible deletion of Ash1l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Firstly, we assessed the impact of global Ash1l loss-of-function on survival and craniofacial skeletal development. The proportion of homozygous Ash1l germline knockout embryos was normal at e18.5, however no live Ash1l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: Ash1l+/+ n = 41, P = 0.00095). Ash1l-/- had shortened nasal bones at e18.5 (n = 31, P = 0.017) compared to heterozygous and wildtype littermates. To assess Ash1l loss-of-function specifically in the cortex, we used a tamoxifen-inducible cre strain to knockout Ash1l early in cortical development (Emx1cre-ERT2; e10.5). We performed immunohistochemistry with antibodies for SATB2, an upper layer marker, and BCL11B, a layer V marker. We found Ash1lcKO had a greater number of SATB2 neurons and they were distributed through the cortical plate (n = 6/genotype, P = 0.0001), whereas BCL11B neurons were similar between genotypes. We performed birthdating of cortical neurons by injected pregnant females with IdU at e14.5 and EdU at e15.5; no differences in neuronal birthdating were identified (n = 4-6/genotype, P = 0.40 for e14.5 and P = 0.057 for e15.5). We utilized single cell RNA sequencing to compare cortical cell populations and identify differentially expressed genes between Ash1lcKO and Ash1lCtrl e18.5 embryos. This revealed numerous differences in gene expression that were sufficient to cluster control and mutant upper layer neurons separately. We found that Ash1lcKO upper layer neurons had altered pseudotime compared to controls, suggesting underlying differences in cell differentiation trajectory. Together, this analysis reveals that ASH1L serves important roles during cortical development, specifically guiding cell fate via gene regulation. Understanding these mechanisms will be fundamental in mitigating Ash1l-associated ASD outcomes and aid in treatment development.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Molecular biology.

Index Term-Uncontrolled  

Autism

Index Term-Uncontrolled  

Histone methyltransferase

Index Term-Uncontrolled  

Cortical development

Index Term-Uncontrolled  

Mouse model

Index Term-Uncontrolled  

Cortical neurons

Added Entry-Corporate Name  

University of Michigan Genetics and Genomics PhD

Host Item Entry  

Dissertations Abstracts International. 85-12B.

Electronic Location and Access  

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Control Number  

joongbu:658010