biostudies-literatureWang QNEI NIH HHSNational Eye InstituteResearch to Prevent BlindnessNational Institutes of HealthBabraham Institute116046https://www.ebi.ac.uk/biostudies/studies/S-EPMC12439348biostudies-literatureUnknown44(8)Although the regulation of branching morphogenesis by spatially distributed cues is well established, the underlying intracellular signaling mechanisms are not well understood. The development of the lacrimal gland is driven by fibroblast growth factor (FGF) signaling, which activates phospholipase C gamma (PLCγ). Here, we showed that mutating the PLCγ1 binding site on Fgfr2 leads to ectopic branching and hyperplasia in the lacrimal gland, which was phenocopied by either deleting PLCγ1 or disabling any of its SH2 domains. PLCγ1 inactivation did not change the level of Fgfr2 or affect mitogen-activated protein kinase (MAPK) signaling but instead led to sustained AKT phosphorylation due to increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) production. Consistent with this, the PLCγ1 mCell reportsFGF-induced phospholipase Cγ signaling regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism.PMC12439348R01 EY034451P30 EY019007R01 EY018868R01EY031210K99EY032171R01EY018868R01 EY031210BB/Y0006925/1K99 EY0321715P30EY019007R01EY034451Hannan AStephens LTao CAnderson KEPeregrin JLi WWang QMakrides NLin CSZhang XHawkins PDing ZWu YfalseFGF-induced phospholipase Cγ signaling regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism.Although the regulation of branching morphogenesis by spatially distributed cues is well established, the underlying intracellular signaling mechanisms are not well understood. The development of the lacrimal gland is driven by fibroblast growth factor (FGF) signaling, which activates phospholipase C gamma (PLCγ). Here, we showed that mutating the PLCγ1 binding site on Fgfr2 leads to ectopic branching and hyperplasia in the lacrimal gland, which was phenocopied by either deleting PLCγ1 or disabling any of its SH2 domains. PLCγ1 inactivation did not change the level of Fgfr2 or affect mitogen-activated protein kinase (MAPK) signaling but instead led to sustained AKT phosphorylation due to increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) production. Consistent with this, the PLCγ1 m2025-01-01T00:00:00Z2025 Aug2026-06-01T15:43:29.196Z2026-04-08T13:42:58.939ZS-EPMC124393484071188310.1016/j.celrep.2025.116046