The Hapln1a‐ECM Influences Sema3d Signal Transduction During Fin Regeneration

Abstract

The zebrafish regenerating fin is an important model system to understand skeletal morphogenesis, the process of how the skeleton achieves its appropriate size and shape. The fin skeleton is comprised of multiple bony fin rays where each fin ray is comprised of bony segments separated by joints. Our research on the short fin (sof) mutant revealed that the gap junction protein Connexin43 (Cx43) coordinates bone growth and skeletal patterning. Downstream mediators of Cx43 function include the secreted signaling molecule Semaphorin3d (Sema3d) and the link protein Hyaluronan and Proteoglycan Link Protein 1a (Hapln1a). Hapln1a stabilizes the hyaluronan (HA) and proteoglycan network in the extracellular matrix (ECM). We suggest that components of the Hapln1a ECM, including HA and the proteoglycan Aggrecan (Acan), influence the ability of Sema3d to interact with its cell surface receptors to mediate cell proliferation and joint formation. Indeed, knockdown of Hapln1a destabilizes HA, Acan, and strikingly, Sema3d. Thus, HA and/or Acan may be required for the presentation of Sema3d to its receptors. Moreover, we find that hapln1a and sema3d interact genetically, suggesting that the Hapln1a and Sema3d gene products function in common pathways to coordinate skeletal growth and patterning. These findings provide the first evidence that the Hapln1a-ECM regulates Sema3d signal transduction in vivo. Moreover, these findings reveal tangible connections between the Hapln1a-ECM, signal transduction, and skeletal morphogenesis. This research was supported by the NSF.