Dissecting the role of AUTS2 and GALNT17 in neurodevelopment using a mouse model for human AUTS2 syndrome

Autism spectrum disorders (ASD) are prevalent neurological disorders, and classically characterized by inappropriate social interaction and stereotypic behavior with additional phenotypes, including intellectual disability (ID), developmental delay, feeding difficulties, epilepsy, microcephaly, and craniofacial abnormalities. Moreover, the severity of each of these phenotypes in individual ASD patients varies dramatically, because most ASD cases are multigenic, involving mutations in a wide variety of heterogenous genes; many cases involve copy number variations, which impact neighboring genes either directly or through disruption of shared long-range regulatory elements. One more recently uncovered ASD candidate gene, Autism Susceptibility Candidate 2 (AUTS2), and it was first discovered as the gene disrupted by reciprocal translocation in human twins with ASD and ID. Most reported patients have been shown to carry genomic rearrangements within or containing AUTS2. All patients described so far display a combination of comorbid phenotypes, which have been collectively described as the “AUTS2 syndrome.” ID and developmental delay are core features of the AUTS2 syndrome, with some mixture of frankly autistic behaviors, feeding difficulties, epilepsy, microcephaly and craniofacial abnormalities also commonly found. Although there are some Auts2 knockout (KO) animal models available, the role for AUTS2 in these phenotypes has not been fully explicated. Moreover, most reported patients have been shown to carry genomic rearrangements involving the larger AUTS2 region, which further suggests a possible role for the nearest neighbor of AUTS2, GALNT17. GALNT17 encodes a brain-expressed N-acetylgalactosaminyl transferase (GalNAc-T), which is involved in O-linked glycosylation. This type of post-translational modification is important for neurodevelopment, because it mediates cell adhesion, cell-cell interaction, neurite outgrowth, and cell signaling. The GALNT17 gene was previously named WBSCR17, because it is located at the distal edge of a region that is commonly deleted or duplicated in Williams- Beuren Syndrome (WBS), a developmental disorder with motor and coordination problems, impaired visuospatial memory, and abnormal social interaction. Although GALNT17 is not located within the WBS critical region (WBSCR), the genes flanking the WBSCR are often looped together in nuclear chromatin, and interact with AUTS2 in a long-range regulatory domain. These results, in addition to our evidence that Auts2 and Galnt17 are co-expressed in brain, suggest that Galnt17 is involved in neurodevelopment, and possibly interacts with Auts2. However, there is little known about the role of GALNT17 at molecular level or in the brain. To study the etiology of human AUTS2 syndrome, we have identified a mouse model called 16Gso (T(5:8)16Gso). 16Gso mice carry a chromosomal translocation between Chromosomes 5 and 8 to disrupt the long-range regulatory structure in the Auts2 – Galnt17 region. In studies presented in this thesis, we found that 16Gso homozygotes recapitulate the behavioral, and cerebellar and hippocampal neuropathological phenotypes of AUTS2 syndrome patients. We also showed Galnt17 knockout homozygotes displayed both AUTS2 syndrome and WBS phenotypes, and that Galnt17 is involved in cerebellar development with disruption of glycosylation and galactose metabolism. Furthermore, we performed genetic complementation tests to dissect the contributions of Auts2 and Galnt17 in AUTS2 syndrome and WBS phenotypes, especially ID and autistic behavior. The data suggests that both Auts2 and Galnt17 contribute to 16Gso phenotypes, and provides new information that may be directly relevant to the etiology of the overlapping symptoms of human AUTS2 syndrome and WBS.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2020

Author dc:creator

• Chen, Chih-Ying

Contributors dc:contributor

• Stubbs, Lisa
• Ceman, Stephanie
• Gillette, Martha
• Raetzman, Lori

• AUTS2
• GALNT17
• Autism
• ASD
• AUTS2 syndrome
• glycosylation
• Williams- Beuren Syndrome
• WBS

Statement dc:rights

• Copyright 2020 Chih-Ying Chen

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/108661

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/108661