A narrow time-window for WNT, EDA, and SHH signaling during postnatal sweat gland development.

Sweat gland development requires tightly coordinated signaling between multiple gene regulatory networks; however, the timing control of these pathways during postnatal maturation remains poorly defined. X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by pathogenic variants of the ectodysplasin A gene (EDA), exemplifies the clinical consequences of disrupted sweat gland development. In this study, we investigated the postnatal expression dynamics of wingless (WNT), EDA, and sonic hedgehog (SHH) signaling during murine sweat gland maturation. By using immunohistochemical analysis of ventral paw skin from wild-type and Eda-deficient Tabby mice, we demonstrate that phospho-LRP6 (representing the WNT pathway), EDA, and SHH are simultaneously active within a narrowly defined time slot between postnatal day 1 and day 5, corresponding to ductal extension and early secretory maturation of the sweat gland. Disruption of EDA signaling was associated with markedly reduced postnatal WNT activity, suggesting reciprocal regulatory interactions rather than a strictly linear signaling hierarchy. Notably, postnatal SHH activity was accompanied by Gli2, but not Gli1, indicating a gene-specific hedgehog transcriptional program during sweat gland maturation. These findings identify a critical postnatal signaling window and provide insight into why postnatal EDA administration failed to restore sweat gland development in XLHED patients.