A global gene regulatory program and its region-specific regulator partition neurons into commissural and ipsilateral projection types

Author:

Masuda Aki1ORCID,Nishida Kazuhiko2ORCID,Ajima Rieko1,Saga Yumiko1ORCID,Bakhtan Marah3ORCID,Klar Avihu3ORCID,Hirata Tatsumi1ORCID,Zhu Yan1ORCID

Affiliation:

1. National Institute of Genetics, Graduate University for Advanced Studies, Sokendai, Yata 1111, Mishima, Shizuoka 411-8540, Japan.

2. Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.

3. Department of Medical Neurobiology, IMRIC, Hebrew University - Hadassah Medical School, Jerusalem, Israel.

Abstract

Understanding the genetic programs that drive neuronal diversification into classes and subclasses is key to understand nervous system development. All neurons can be classified into two types: commissural and ipsilateral, based on whether their axons cross the midline or not. However, the gene regulatory program underlying this binary division is poorly understood. We identified a pair of basic helix-loop-helix transcription factors, Nhlh1 and Nhlh2, as a global transcriptional mechanism that controls the laterality of all floor plate–crossing commissural axons in mice. Mechanistically, Nhlh1/2 play an essential role in the expression of Robo3, the key guidance molecule for commissural axon projections. This genetic program appears to be evolutionarily conserved in chick. We further discovered that Isl1, primarily expressed in ipsilateral neurons within neural tubes, negatively regulates the Robo3 induction by Nhlh1/2. Our findings elucidate a gene regulatory strategy where a conserved global mechanism intersects with neuron class–specific regulators to control the partitioning of neurons based on axon laterality.

Publisher

American Association for the Advancement of Science (AAAS)

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