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Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex

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Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing

Lei Xing¹, Nereo Kalebic², Takashi Namba¹

¹Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.

|October 20, 2020

Summary

Serotonin (5-HT) signaling through HTR2A receptor promotes basal progenitor proliferation in the developing neocortex. This mechanism may have driven the evolutionary expansion of the mammalian neocortex.

Keywords:

basal progenitor cell proliferation developing neocortex evolution neocortex expansion neural progenitor cells serotonin serotonin receptor 2A

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Area of Science:

Neuroscience
Developmental Biology
Evolutionary Biology

Background:

Neocortex expansion in mammals correlates with increased basal progenitor (BP) proliferation.
BP proliferation is regulated by intrinsic and extrinsic signals, but the role of neurotransmitters is unclear.

Purpose of the Study:

To investigate the role of serotonin (5-HT) and its receptor HTR2A in regulating basal progenitor proliferation during neocortex development.
To determine if this signaling pathway contributed to the evolutionary expansion of the mammalian neocortex.

Main Methods:

Comparative analysis of HTR2A expression and response in embryonic mouse, ferret, and human neocortex.
Utilized CRISPR/Cas9 gene editing to knock out HTR2A in ferrets.
Employed pharmacological activation of HTR2A in ex vivo human neocortex cultures.

Main Results:

Serotonin (5-HT) signaling via HTR2A promotes basal progenitor proliferation in an evolutionarily relevant manner.
HTR2A is not expressed in embryonic mouse neocortex, and 5-HT does not increase mouse BP proliferation unless HTR2A is ectopically expressed.
Knocking out HTR2A in ferret neocortex reduced BP proliferation, while activating it in human neocortex increased proliferation via HER2/ERK signaling.

Conclusions:

Serotonin (5-HT) acts as a crucial extrinsic pro-proliferative signal for basal progenitors in the developing neocortex.
The HTR2A-mediated signaling pathway likely played a significant role in the evolutionary expansion of the mammalian neocortex.