MICRORNA-19B-MEDIATED REGULATORY MECHANISMS IN CHICK PALLIUM DEVELOPMENT

Feingold Syndrome Type 2 (FS2), caused by MIR17HG (miR-17~92 cluster) haploinsufficiency, is frequently associated with microcephaly, yet the mechanistic basis linking microRNA dysfunction to impaired brain growth remains poorly understood. Among the six microRNAs in this cluster, miR-19b emerges as a key regulator of neural progenitor proliferation and neuronal differentiation. Building upon our recent discovery that miR-19b orchestrates proliferation dynamics and pallial patterning in the developing avian forebrain. We propose a conserved mechanism through which loss of miR-19b function may contribute to microcephaly in FS2. In the embryonic chick pallium, miR-19b maintains neural stem cell proliferation by repressing the cell-cycle inhibitor E2f8 and simultaneously prevents premature neuronal differentiation through suppression of NeuroD1. Loss-of-function of miR-19b leads to decreased proliferation, precocious cell-cycle exit, and abnormal specification of deep-layer–like neuronal subtypes—developmental disturbances analogous to those observed in microcephalic mammalian models. Because the miR-17~92 cluster plays an evolutionarily conserved role in expanding neural progenitors, our findings suggest that reduced miR-19b activity in FS2 disrupts the balance between progenitor renewal and differentiation, resulting in early depletion of the neural progenitor pool and reduced brain size. Thus, miR-19b represents a critical molecular node connecting miRNA cluster dosage to cortical growth, offering mechanistic insights into the etiology of FS2-associated microcephaly and identifying potential therapeutic avenues for restoring progenitor homeostasis.