Journal Club (November 15, 2021)

Nature Article Published: 01 October 2021 volume 598, pages483–488 (2021)
Regulation of prefrontal patterning and connectivity by retinoic acid (レチノイン酸による前頭前野の形態形成と神経回路の制御)
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*

  • Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
  • Department of Genetics, Yale School of Medicine, New Haven, CT, USA
  • Yale Genome Editing Center, Yale School of Medicine, New Haven, CT, USA
  • Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
  • Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
  • Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT, USA
  • Kavli Institute for Neuroscience, Yale University, New Haven, CT, USA

*Nenad Sestanは、Yale大学医学部の教授である。

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 rodents6,7,8,9, 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 function12,13,14,15, 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.






01 October 2021
The genetic symphony underlying evolution of the brain’s prefrontal cortex
The prefrontal cortex of the human brain is larger than that of other species. Comparisons of mouse, macaque and human brains uncover some of the genetic and molecular factors behind these differences.
Jenelle L. Wallace & Alex A. Pollen


3D Illustration Concept of Central Organ of Human Nervous System Brain Lobes Frontal Lobe Described with Labels Anatomy



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