Alain C. Burette ^1,2* Hanna Vihma ^1,2 Audrey L. Smith ^1,2 Siddhi S. Ozarkar ^1,2 Jeff Bennett ^3,4 David Amaral ^3,4 Benjamin D. Philpot ^1,2,5

• ¹ Neuroscience Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ² Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ³ Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Sacramento, California, United States
• ⁴ California National Primate Research Center, University of California, Davis, Davis, California, United States
• ⁵ Carolina Institute for Developmental Disabilities, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

Transcription factor 4 (TCF4) has been implicated in a range of neuropsychiatric disorders, including major depressive disorder, bipolar disorder, and schizophrenia. Mutations or deletions in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare neurodevelopmental disorder. A detailed understanding of its spatial expression across the developing brain is necessary for comprehending TCF4 biology and, by extension, to develop effective treatments for TCF4-associated disorders. However, most current knowledge is derived from mouse models, which are invaluable for preclinical studies but may not fully capture the complexities of human neuropsychiatric phenotypes. This study compared TCF4 expression in the developing mouse brain to its regional and cellular expression patterns in normal prenatal, neonatal, and young adult rhesus macaque brains, a species more relevant to human neurodevelopment. While the general developmental expression of TCF4 is largely conserved between macaques and mice, we saw several interspecies differences. Most notably, a distinct layered pattern of TCF4 expression was clear in the developing macaque neocortex but largely absent in the mouse brain. High TCF4 expression was seen in the inner dentate gyrus of adult mice but not in macaques. Conversely, TCF4 expression was higher in the adult macaque striatum compared to the mouse striatum. Further research is needed to show the significance of these interspecies differences. Still, they underscore the importance of integrating rodent and primate studies to comprehensively understand TCF4 function and its implications for human disorders. Moreover, the primate-specific expression patterns of TCF4 will inform genetic and other therapeutic strategies to treat TCF4-associated disorders.