Summary: New research identifies an unexpected developmental role for serotonin in human neocortex formation. Serotonin functions outside cells as a growth factor for basal progenitors in the developing human neocortex, and placenta-derived serotonin may have contributed to the evolutionary enlargement of the human neocortex.
Source: Max Planck Society
Throughout human evolution the brain increased in size, particularly in the neocortex—the region responsible for higher cognitive functions such as language, complex thought, planning and imagination. Investigators at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, collaborating with clinicians at the University Hospital Carl Gustav Carus Dresden, have been studying molecular drivers of neocortical expansion. Previous work identified intrinsic regulators acting within basal progenitors, the neural stem cells in the developing neocortex that are central to its growth. The new study reveals an additional, extrinsic influence: serotonin produced by the placenta acts as a growth factor for basal progenitors in the developing human neocortex, a mechanism absent in mice and likely relevant to human brain evolution.
The team led by Wieland Huttner, a founding director of the institute, examined whether neurotransmitters can influence neurodevelopmental processes that shape cortical size. Serotonin—a neurotransmitter widely known for its roles in mood and well-being—also circulates in the developing embryo. In both humans and mice the placenta synthesizes serotonin that reaches the fetal brain via the bloodstream, but the developmental function of this placental serotonin had not been established.
Postdoctoral researcher Lei Xing, who previously studied neurotransmitters during his doctoral work, mined existing datasets from the Huttner laboratory and found a key difference between species: the serotonin receptor HTR2A is expressed in the developing human neocortex but is not present in the embryonic mouse neocortex. Because serotonin activates signaling only after binding to receptors such as HTR2A, this observation suggested a possible species-specific pathway that might help explain differences in cortical development.
To test the hypothesis, the researchers experimentally introduced HTR2A expression into the embryonic mouse neocortex. Activation of this receptor by serotonin triggered downstream signaling pathways that increased the production of basal progenitors. An elevated number of basal progenitors can generate more cortical neurons, a cellular route that supports expansion of the neocortex. Complementary experiments showed that removing endogenous HTR2A in ferret embryonic cortex reduced basal progenitor proliferation, reinforcing the receptor’s functional role in species with a more developed neocortex.
Significance for brain development and evolution
“Our study reveals a previously unrecognized role for serotonin as an extrinsic growth-promoting signal for basal progenitors in highly developed mammalian brains, notably human,” summarizes Wieland Huttner. The findings place serotonin among important extrinsic cues that regulate basal progenitor proliferation during cortical development and suggest that placental serotonin signaling via HTR2A may have been one factor contributing to evolutionary neocortical expansion.
The work also has potential clinical relevance. Abnormal serotonin signaling and altered expression or mutation of HTR2A have been associated with several neurodevelopmental and psychiatric conditions, including Down syndrome, attention-deficit/hyperactivity disorder and autism. Understanding how serotonin and HTR2A influence fetal brain development could clarify mechanisms that underlie congenital brain disorders and inform future therapeutic strategies.
About this neuroscience research news
Source: Max Planck Society
Contact: Press Office – Max Planck Society
Image: The image is credited to Lei Xing et al., Neuron 2020 / MPI-CBG
Original Research: Closed access.
“Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex” by Lei Xing et al., published in Neuron.
Abstract
Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex
Highlights
- • The serotonin receptor HTR2A is expressed in developing human and ferret neocortex but not in embryonic mouse neocortex.
- • HTR2A is both necessary for and sufficient to increase basal progenitor (BP) proliferation in species that express the receptor.
- • Activation of HTR2A shifts basal progenitors toward a more proliferative state, reducing the fraction committed to immediate neurogenesis.
- • HER2 and ERK1/2 signaling pathways mediate the pro-proliferative effect of HTR2A activation on basal progenitors.
Summary
Expansion of the mammalian neocortex during evolution has been linked to increases in the number and proliferative capacity of basal progenitors in the subventricular zone. While several intrinsic and extrinsic regulators of BP proliferation are known, the potential contribution of classical neurotransmitters as extrinsic signals had not been clearly defined. This study demonstrates that serotonin (5-HT), acting through HTR2A, promotes BP proliferation in an evolutionarily relevant manner. HTR2A is absent from embryonic mouse neocortex, and serotonin does not enhance mouse BP proliferation unless HTR2A is ectopically expressed. Conversely, CRISPR/Cas9 knockout of endogenous HTR2A in embryonic ferret cortex decreases BP proliferation. Pharmacological activation of endogenous HTR2A in fetal human neocortex ex vivo increases BP proliferation via HER2/ERK signaling. These results identify serotonin as an important extrinsic pro-proliferative signal for basal progenitors and suggest a potential role for placental serotonin signaling in neocortical expansion during evolution.