Lipid-mediated reinforcement of FGF/MAPK signaling enables robust otic placode specification

Abstract The formation of cranial placodes requires groups of ectodermal cells to interpret inductive signals in a robust and organized manner, yet how signaling responses are coordinated across a developing field remains incompletely understood. During otic placode specification, fibroblast growth factor (FGF) signaling must overcome intrinsic noise and rising inhibitory feedback to drive collective transcriptional responses, suggesting the existence of reinforcing regulatory events beyond ligand–receptor interactions and gene regulatory networks alone. Here we identify the secreted lipid-binding protein Apolipoprotein D (APOD) as an essential mediator of otic placode specification that links lipid-dependent regulation to FGF/MAPK signaling during early development. We find that APOD is strongly expressed in the forming otic placode, where it is necessary for otic specification and morphogenesis. Loss of APOD attenuates ERK1/2 activation, indicating impaired cellular responsiveness to FGF/MAPK signaling. Notably, FGF signaling induces APOD expression, establishing a positive feedback loop that reinforces signaling at the tissue level. These findings reveal lipid-mediated regulation of cell signaling as a critical mechanism enabling robust interpretation of developmental signals during sensory placode formation. More broadly, our work highlights lipid management as a key organizational principle by which embryonic tissues achieve coordinated responses to morphogenetic cues. Highlights The lipocalin Apolipoprotein D (APOD) is expressed transiently during early otic development APOD is required for specification and morphogenesis of the otic placode APOD functions upstream MAPK activation during otic specification FGF induces APOD expression to build a positive feedback loop Graphical Abstract