Rackley, A. | bioRxiv Science

bioRxiv2026

Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling

Autosomal dominant gain-of-function mutations in platelet-derived growth factor receptor beta (PDGFRb) cause overgrowth of the skeleton and other connective tissue in Kosaki overgrowth syndrome. However, the target cell type and signaling pathways underlying PDGFRb-driven overgrowth are unknown. Normal postnatal growth is controlled by pituitary-secreted growth hormone (GH), which activates the STAT5 transcriptional factor to upregulate insulin-like growth factor 1 (IGF1). To investigate the role of the GH-STAT5-IGF1 pathway in PDGFRb-related overgrowth, we generated mice with a PDGFRb gain-of-function mutation in skeletal and fibroblast lineages, which resulted in STAT5 activation and gigantism. Conditional deletion of Stat5ab in connective tissue lineages rescued skeletal overgrowth and keloid-like fibrosis in the skin. Conditional deletion of GH receptor (Ghr) did not rescue overgrowth, indicating the physiological activator of STAT5 is not required for overgrowth. However, deletion of Igf1, the STAT5 target gene, and its receptor, Igf1r, in connective tissue, rescued the overgrowth phenotype. These findings demonstrate a GHR-independent STAT5-IGF1 signaling pathway in mutant connective tissue cells, which mediates PDGFRb-driven overgrowth in mice and potentially in humans with similar PDGFRB mutations.

genetics↗

bioRxiv2025

Mouse scalp development requires Rac1 and SRF for the maintenance of mechanosensing mesenchyme

Regulation of essential cellular responses like proliferation, migration, and differentiation is crucial for normal development. Rac1, a ubiquitously expressed small GTPase, executes these responses under the regulation of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GTPases). Mutations in specific GEFs (DOCK6) and GTPases (AHGAP31) that regulate Rac1 are associated with Adams-Oliver syndrome (AOS), a developmental syndrome characterized by congenital scalp defects and limb truncations. Genetic ablation of Rac1 in the mouse embryonic limb ectoderm results in limb truncation. However, the etiology of Rac1-associated cranial defects is unknown. To investigate the origin and nature of cranial defects, we used a mesenchymal Cre line (Pdgfra-Cre) to delete Rac1 in cranial mesenchyme. Rac1-KO mice died perinatally and lacked the apical portion of the calvarium and overlying dermis, resembling cranial defects seen in severe cases of AOS. In control embryos, -smooth muscle actin (SMA) expression was spatially restricted to the apical mesenchyme, suggesting a mechanical interaction between the growing brain and the overlying mesenchyme. In Rac1-KO embryos there was reduced proliferation of apical mesenchyme, and reduced expression of SMA and its regulator, serum response factor (SRF). Remarkably, Srf-KO mice generated with Pdgfra-Cre recapitulated the cranial phenotype observed in Rac1-KO mice. Together, these data suggest a model where Rac1 and SRF are critical to maintaining apical fibroblasts in a mechano-sensitive and proliferative state needed to complete cranial development.

developmental biology↗