Abstract
While the function of proteins and genes has been widely studied during vertebrate development, relatively little work has addressed the role of carbohydrates. Hyaluronan (HA), also known as hyaluronic acid, is an abundant carbohydrate in embryonic tissues and is the main structural component of the extracellular matrix of epithelial and mesenchymal cells. HA is able to absorb large quantities of water and can signal by binding to cell-surface receptors. During organ development and regeneration, HA has been shown to regulate cell proliferation, cell shape, and migration. Here, we have investigated the function of HA during molar tooth development in mice, in which, similar to humans, new molars sequentially bud off from a pre-existing molar. Using an ex vivo approach, we found that inhibiting HA synthesis in culture leads to a significant increase in proliferation and subsequent size of the developing molar, while the formation of sequential molars was inhibited. By cell shape analysis, we observed that inhibition of HA synthesis caused an elongation and reorientation of the major cell axes, indicating that disruption to cellular orientation and shape may underlie the observed phenotype. Lineage tracing demonstrated the retention of cells in the developing first molar (M1) at the expense of the generation of a second molar (M2). Our results highlight a novel role for HA in controlling proliferation, cell orientation, and migration in the developing tooth, impacting cellular decisions regarding tooth size and number.
Highlights
During development, the extracellular matrix plays a crucial role in controlling the growth and size of diverse organs (Jafari et al, 2010; Walker et al, 2018)
We studied the function of HA during successional molar development in mice
The molar region was exposed to an inhibitor of HA synthesis when the M1 was at the cap stage and the molar 2 germ (M2) was forming from the tail of the M1
Summary
The extracellular matrix plays a crucial role in controlling the growth and size of diverse organs (Jafari et al, 2010; Walker et al, 2018). Carbohydrates are important components of this matrix; their role is poorly studied in developmental biology. Hyaluronan (HA), known as hyaluronic acid, is a polymeric carbohydrate and a major component of the extracellular matrix. HA is distributed widely throughout the connective and Hyaluronan in Tooth Development epithelial tissues and can absorb large quantities of water, regulating the swelling pressure for tissue rigidity and biomechanical integrity (Toole, 2001; Spicer and Tien, 2004). Apart from this structural role, HA can interact with cell-surface receptors and activate the HA signaling pathway. HA is abundant in tissues that proliferate and grow during embryogenesis, regeneration, and carcinogenesis, as it provides the conditions for cell migration and proliferation, thereby promoting tissue remodeling (Chen and Abatangelo, 1999; Jiang et al, 2007; Contreras et al, 2009; Preston and Sherman, 2011)
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