Excitatory neurons as the default fate in bifurcation of excitatory and inhibitory neuron lineages

Wang, M.; Qiu, X.-Y.; Duan, Y.-B.; Tang, X.; Lu, Q.; Li, Y.; Qin, H.-W.; Long, X.-T.; Jin, M.-M.; Fan, P.-Y.; Zhang, H.; Li, Y.-N.; He, J.

doi:10.1101/2025.10.29.685327

bioRxiv · 10.1101/2025.10.29.685327

Excitatory neurons as the default fate in bifurcation of excitatory and inhibitory neuron lineages

Wang, M.·Qiu, X.-Y.·Duan, Y.-B.·Tang, X.·Lu, Q.·Li, Y.·Qin, H.-W.·Long, X.-T.·Jin, M.-M.·Fan, P.-Y.·Zhang, H.·Li, Y.-N.·He, J.

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Abstract

In the brain, a precise excitation-inhibition balance underpins every neural operation. Strikingly, across the vertebrate CNS, excitatory and inhibitory neurons often emerge from common progenitors (termed EX-IN lineage), yet how such dichotomous fates diverge has remained enigmatic. Here, exploiting spinal v2a (excitatory)-v2b (inhibitory) and retinal bipolar (excitatory) - amacrine (inhibitory) lineages as EX-IN lineage paradigm, we report a single, conserved genetic program: excitatory neural fate is the default state when sibling-cell communication is silenced; progenitor- and excitatory neuron-expressed homeobox genes actively repress the inhibitory program, while Notch signaling releases this repression to unleash inhibitory identity. Thus, we define a unifying principle governing EX-IN lineage divergence that generate the fundamental dichotomy of neural circuits.

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Wang, M., Qiu, X.-Y., Duan, Y.-B., Tang, X., Lu, Q., Li, Y., Qin, H.-W., Long, X.-T., Jin, M.-M., Fan, P.-Y., Zhang, H., Li, Y.-N., He, J.. 2025-10-29. Excitatory neurons as the default fate in bifurcation of excitatory and inhibitory neuron lineages. https://doi.org/10.1101/2025.10.29.685327

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