Growth Factor/Extracellular Matrix Interactions During Branching Morphogenesis

National Institute Of Dental & Craniofacial Research

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Abstract

The exquisite control of growth factor signaling by HS is dictated by the tremendous structural heterogeneity of its sulfated modifications. Heparan sulfotransferase enzymes generate highly 3-O-sulfated epitopes on cell surfaces and in the extracellular matrix. Functional redundancy exists among the family of seven enzymes, but Hs3st3a1 and Hs3st3b1 sulfated HS increases epithelial FGFR signaling and morphogenesis. Single-cell RNAseq analysis of control SMGs identifies increased expression of Hs3st3a1 and Hs3st3b1 in endbud and myoepithelial cells, both of which are progenitor cells during development and regeneration. To analyze their in vivo functions, we generated both Hs3st3a1-/- and Hs3st3b1-/- single knockout mice. Salivary glands from both mice have impaired fetal epithelial morphogenesis and reduced 3-O-sulfated HS in the basement membrane. HS disaccharide analysis showed increased N- and non-sulfated disaccharides in Hs3st3a1-/- HS. Analysis of adult KO gland function revealed there was an increase in frequency of drinking behavior in both KO mice, suggesting basal salivary hypofunction, possibly due to myoepithelial dysfunction. Understanding how 3-O-sulfation regulates FGFR-dependent myoepithelial progenitor function will be important to manipulate HS-binding growth factors to enhance tissue function and regeneration. Our goal is to use genetics to understand the 3-O-sulfated code of HS. This information will be useful to manipulate cellular specificity of HS-binding growth factors and fine-tune biological responses, enhancing progenitor expansion for tissue regeneration. While we focus on the salivary gland, the mouse phenotypes direct us to investigate earlier stages of embryo development and to compare other organs that are affected. These mice are important tools to analyze 3-O-sulfation in salivary gland progenitors and to better understand the fine tuning of cellular responses to FGFRs and HS modifications.