Abstract
Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function “feeds back” to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology.
Highlights
It is well established that embryogenesis and cell specification can be controlled by developmental morphogens and sequential, tissue-specific changes in gene expression
We showed that kidney morphogenesis in the zebrafish is dependent on collective epithelial cell migration toward the proximal pole of the nephron
We found that the Notch pathway mutant mindbomb [14] lacked normal proximally directed pronephric epithelial migration. mindbomb homozygotes exhibited significantly reduced cell proliferation in the distal tubule compared with wild-type siblings, further supporting the conclusion that distal tubule proliferation is stimulated by epithelial cell migration and resulting longitudinal stretch (Fig. 2 C, D)
Summary
It is well established that embryogenesis and cell specification can be controlled by developmental morphogens and sequential, tissue-specific changes in gene expression. It is clear that to achieve the higher order structure during organ morphogenesis, cell fate specification must be linked to cell rearrangement, migration, and other physical processes that determine the ultimate organ shape and function [1,2]. Vascular shear force in capillaries is required for remodeling the glomerulus and formation of the glomerular capillary tuft that initiates blood filtration [10]. We have previously shown that fluid shear force in the lumen of zebrafish kidney tubules is required for nephron morphogenesis as it initiates collective tubule cell migration that accounts for the convoluted shape of mature proximal tubules and the final position of nephron segment boundaries [12]. The findings indicate that physical interactions between cells guide complex morphogenetic processes during kidney organogenesis and that final kidney form is governed by kidney function
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