Metabolic and Thalamic Signals Instruct Radial Glia Fate Decisions in Human Cortex

Researchers mapped metabolism across donated fetal tissue and cortical organoids, revealing that radial glia depend on the pentose phosphate pathway to sustain rapid proliferation. Reducing glucose availability or inhibiting the pathway shifted output toward later-born inhibitory neurons, demonstrating that nutrient processing actively directs cell fate rather than merely supporting it. Parallel assembloid experiments showed thalamic fibers arriving weeks before synaptogenesis deliver instructive cues that bias radial glia toward excitatory neuron production. These dual inputs explain how the human cortex achieves its expanded neuronal diversity and prolonged neurogenic window compared with other primates. The findings link maternal metabolic stress and early connectivity defects to specific neurodevelopmental disorders and suggest metabolism-targeted interventions could be tested in organoids within two years to rescue cortical malformations.