Tcf4 dysfunction alters dorsal and ventral cortical neurogenesis in Pitt-Hopkins syndrome mouse model showing sexual dimorphism

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 5; p. 167178
• Main Authors: Espinoza, Francisca, Carrazana, Ramón, Retamal-Fredes, Eduardo, Ávila, Denisse, Papes, Fabio, Muotri, Alysson R., Ávila, Ariel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2024
• Subjects: Animals; ASD; Cerebral cortex; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Disease Models, Animal; Facies; Female; Haploinsufficiency; Hyperventilation - genetics; Hyperventilation - metabolism; Hyperventilation - pathology; Intellectual Disability - genetics; Intellectual Disability - metabolism; Intellectual Disability - pathology; Interneurons; Interneurons - metabolism; Interneurons - pathology; Male; Mice; Neurogenesis; Pitt-Hopkins syndrome; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; Sex Characteristics; TCF4; Transcription Factor 4 - genetics; Transcription Factor 4 - metabolism; Pitt-Hopkins syndrome; ASD; Cerebral cortex; TCF4; Interneurons; Neurogenesis
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167178

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies. •Pitt Hopkins syndrome (PTHS) mouse model shows altered progenitor cell dynamics.•Altered cortical neurogenesis in PTHS het mice shows sexual dimorphism.•Populations of cortical excitatory and inhibitory neurons are altered in PTHS mice.