Cell expansion for notochord mechanics and endochondral bone lengthening in zebrafish depends on the 5'-inositol phosphatase Inppl1a.

Cell size is a key contributor to tissue morphogenesis. As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10 to 20 times in size to drive lengthening of endochondral bone. Similarly, notochord vacuolated cells expand to one of the largest cell types in the developing embryo to drive axial extension. In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion. When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition, resulting in adult spines with misshapen vertebral bones and scoliosis. However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5'-inositol phosphatase gene, inppl1a, regulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate that inppl1a-dependent vacuolated cell expansion is essential to establish normal mechanical properties of the notochord and to facilitate the development of a straight spine. Finally, we find that inppl1a is also important for hypertrophic chondrocyte differentiation and endochondral bone lengthening in fish, as has been shown in the human INPPL1-related endochondral bone disorder, opsismodysplasia. Overall, this work reveals a shared mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.