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bioRxiv · 10.1101/2019.12.31.891036

Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid

Shibata, M.·Pattabiraman, K.·Lorente-Galdos, B.·Andreijevic, D.·Xing, X.·Sousa, A. M. M.·Santpere, G.·Sestan, N.
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Abstract

The prefrontal cortex (PFC) and its reciprocal connections with the mediodorsal thalamus (MD) are crucial for cognitive flexibility and working memory1-4 and are thought to be altered in several disorders such as autism spectrum disorder5, 6 and schizophrenia6-9. While developmental mechanisms governing regional patterning of the rodent cerebral cortex have been characterized10-15, the mechanisms underlying the development of PFC-MD connectivity and the lateral expansion of PFC with distinct granular layer 4 in anthropoid primates16-23 have not been elucidated. Here we report increased concentration of retinoic acid (RA), a signaling molecule involved in brain development and function24, 25 in the prospective PFC areas of human and macaque, compared to mouse, during mid-fetal development, a crucial period for cortical circuit assembly. In addition, we observed the lateral expansion of RA synthesizing enzyme, ALDH1A3, expression in mid-fetal macaque and human frontal cortex, compared to mouse. Furthermore, we found that enrichment of RA signaling is restricted to the prospective PFC by CYP26B1, a gene encoding an RA-catabolizing enzyme upregulated in the mid-fetal motor cortex. Gene deletion in mice revealed that RA signaling through anteriorly upregulated RA receptors, Rxrg and Rarb, and Cyp26b1-dependent catabolism is required for the proper molecular patterning of PFC and motor areas, the expression of the layer 4 marker RORB, intra-PFC synaptogenesis, and the development of reciprocal PFC-MD connectivity. Together, these findings reveal a critical role for RA signaling in PFC development and, potentially, its evolutionary expansion.

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Shibata, M., Pattabiraman, K., Lorente-Galdos, B., Andreijevic, D., Xing, X., Sousa, A. M. M., Santpere, G., Sestan, N.. 2019-12-31. Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid. https://doi.org/10.1101/2019.12.31.891036

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