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Regulation of prefrontal patterning and connectivity by retinoic acid

Author

Listed:
  • Mikihito Shibata

    (Yale School of Medicine)

  • Kartik Pattabiraman

    (Yale School of Medicine
    Yale School of Medicine)

  • Belen Lorente-Galdos

    (Yale School of Medicine)

  • David Andrijevic

    (Yale School of Medicine)

  • Suel-Kee Kim

    (Yale School of Medicine)

  • Navjot Kaur

    (Yale School of Medicine)

  • Sydney K. Muchnik

    (Yale School of Medicine
    Yale School of Medicine)

  • Xiaojun Xing

    (Yale School of Medicine
    Yale School of Medicine)

  • Gabriel Santpere

    (Yale School of Medicine
    Universitat Pompeu Fabra)

  • Andre M. M. Sousa

    (Yale School of Medicine
    University of Wisconsin–Madison
    University of Wisconsin–Madison)

  • Nenad Sestan

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

Abstract

The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory1 and are thought to be altered in disorders such as autism2,3 and schizophrenia4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents6–9, the mechanisms that underlie the development of PFC–mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function12–15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC–mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.

Suggested Citation

  • Mikihito Shibata & Kartik Pattabiraman & Belen Lorente-Galdos & David Andrijevic & Suel-Kee Kim & Navjot Kaur & Sydney K. Muchnik & Xiaojun Xing & Gabriel Santpere & Andre M. M. Sousa & Nenad Sestan, 2021. "Regulation of prefrontal patterning and connectivity by retinoic acid," Nature, Nature, vol. 598(7881), pages 483-488, October.
  • Handle: RePEc:nat:nature:v:598:y:2021:i:7881:d:10.1038_s41586-021-03953-x
    DOI: 10.1038/s41586-021-03953-x
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    Cited by:

    1. Albert Stuart Reece & Gary Kenneth Hulse, 2023. "Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration," IJERPH, MDPI, vol. 20(4), pages 1-24, February.
    2. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis," IJERPH, MDPI, vol. 19(24), pages 1-57, December.
    3. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "European Epidemiological Patterns of Cannabis- and Substance-Related Congenital Neurological Anomalies: Geospatiotemporal and Causal Inferential Study," IJERPH, MDPI, vol. 20(1), pages 1-35, December.

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