Shared structural alterations, divergent functional responses in salivary and lacrimal glands: A conceptual framework from Cdc42-mediated polarity disruption

Background Exocrine glands can have distinct functional outcomes despite undergoing similar structural alterations. However, the molecular mechanisms through which these common structural changes give rise to gland-specific functional responses are poorly understood. The salivary and lacrimal glands provide useful models for investigating this functional divergence because they share many structural and physiological characteristics, yet they respond differently to pathological stress.Highlight Acinar-cell-specific deletion of the polarity regulator, cell division cycle 42 (Cdc42), provides an experimental model of epithelial polarity disruption that recapitulates shared structural alterations across exocrine glands, including acinar atrophy, luminal remodeling, and increased cell death. Despite these common structural abnormalities, salivary secretion was reduced, whereas tear secretion was increased, suggesting that structural alterations alone do not determine functional outcomes. There are similar patterns of functional divergence during aging, further supporting this concept. In this review, evidence from Cdc42-deficient mice and aging studies were integrated to examine how shared structural alterations give rise to divergent functional outcomes in exocrine glands. The candidate mechanisms underlying gland-specific responses, including epithelial polarity, water and ion transport, epithelial barrier function, neural regulation, inflammation, and the tissue microenvironment, are discussed.Conclusion A conceptual framework is proposed, in which diverse forms of tissue remodeling converge on common structural alterations, and gland-specific response patterns determine downstream functional outcomes. Understanding these response patterns may provide new insights into exocrine gland homeostasis, and they may facilitate the development of therapeutic strategies for gland dysfunction associated with aging and disease.