Investigating the effects of TCF4 mutations during oligodendrocyte development and maturation in a human-derived model of autism spectrum disorder - Project Summary/Abstract
Pitt-Hopkins Syndrome (PTHS) is a rare form of autism spectrum disorder (ASD) characterized by
developmental delay, breathing abnormalities, seizure, lack of speech, and abnormal facies. PTHS is
caused by de novo mutations in Transcription Factor 4 (TCF4), a key transcription factor that
orchestrates multiple neurodevelopmental programs. Previous studies from our laboratory using PTHS
mouse models showed dysregulation in the density of oligodendrocyte progenitor cells (OPCs) and
maturity of functional oligodendrocytes (OLs), which resulted in myelination deficits. However, these
deficiencies have not been studied in the human system. The current proposal centers on exploring the
effects of TCF4 mutations in human OLs generated from patient-derived induced pluripotent stem cells
(iPSCs). Our laboratory has generated a collection of iPSCs that harbor various disease-causing
mutations in TCF4 that result in the expression of putative dominant-negative proteins or
haploinsufficiency. To determine if patient-specific mutations in TCF4 result in dysregulation of the OL
lineage, we differentiated iPSC using a two-dimensional and a three-dimensional OL generating
protocol. The goals for this proposal focus on (1) characterizing the effects of mutations in TCF4 during
oligodendrogenesis and OL maturation in a patient-derived iPSC model, (2) identifying TCF4’s
interactome during OL specification, and (3) generating a platform for pro-myelinating drug screening.
The proposed approach is innovative and significant, as it aims to shed light on the process of
myelination and the genetic regulators that guide OL maturation and survival. Moreover, this proposal
will allow for the develop of 2-D and 3-D human-derived platforms with the capacity to rapidly screen
promising pro-myelinating drugs that could improve patient quality of life. This fellowship will help the
applicant develop the expertise necessary to conduct basic biological, functional and translational
research as an independent investigator in the area of neuropsychiatric and neurodevelopmental
diseases.
