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Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
- Source :
- Nature communications, vol 13, iss 1
- Publication Year :
- 2022
- Publisher :
- eScholarship, University of California, 2022.
-
Abstract
- Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
- Subjects :
- Intellectual and Developmental Disabilities (IDD)
General Physics and Astronomy
Regenerative Medicine
General Biochemistry, Genetics and Molecular Biology
Transcription Factor 4
Stem Cell Research - Nonembryonic - Human
Intellectual Disability
Genetics
Humans
Hyperventilation
2.1 Biological and endogenous factors
Aetiology
Child
Cell Proliferation
Neurons
Pediatric
Multidisciplinary
5.2 Cellular and gene therapies
Neurosciences
General Chemistry
Stem Cell Research
Brain Disorders
Mental Health
Neurological
Stem Cell Research - Nonembryonic - Non-Human
Development of treatments and therapeutic interventions
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature communications, vol 13, iss 1
- Accession number :
- edsair.doi.dedup.....966159a716d0a08effcd44bbc5f6fb65