FGF and MafB regulated cadherin expression drives lamina formation in the auditory hindbrain

Abstract

The avian auditory brainstem contains specialized nuclei critical for sound localization, including the nucleus laminaris (nL), which forms as a single-cell-thick lamina essential for computing interaural time differences. Despite its functional importance, the molecular mechanisms guiding nL lamina formation have remained poorly understood. Here, we identify a signalling cascade involving FGF8, MafB, and cadherin-22 that orchestrates this morphogenetic process. We show that FGF8 is selectively expressed in the developing auditory hindbrain and correlates spatiotemporally with lamina formation in the nL. Disruption of FGF signalling--either via misexpression of FGF8 or dominant-negative FGFR1--perturbs the formation of the nL and alters cadherin-22 expression. In vitro culture experiments further reveal that nL lamination is sensitive to FGF8 dosage, with an optimal concentration required for both FGF8 and MafB expression and correct structural organization. We demonstrate that FGF8 induces MafB, which in turn regulates cadherin-22 expression. Functional disruption of cadherins impairs lamina formation and leads to reduced FGF8 expression, indicating a feedback loop between adhesion and signalling. Cadherin protein expression appears enriched in the dendrites of nL neurons and computational models--both static and dynamic--show that bipolar, dendrite-localized, adhesion can drive laminar architecture as the maximum adhesion configuration. These findings establish a novel molecular and biophysical mechanism for neuronal lamination in the vertebrate hindbrain, showing how local FGF signalling, transcriptional regulation, and dendritic adhesion converge to shape neural circuitry essential for sound localization.