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

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.