Abstract
Pronephros, a developmental model for adult mammalian kidneys (metanephros) and a functional kidney in early teleosts, consists of glomerulus, tubule, and duct. These structural and functional elements are responsible for different kidney functions, e.g., blood filtration, waste extraction, salt recovery, and water balance. During pronephros organogenesis, cell differentiation is a key step in generating different cell types in specific locations to accomplish designated functions. However, it is poorly understood what molecules regulate the differentiation of different cell types in different parts of the kidney. Two types of epithelial cells, multi-cilia cells and principal cells, are found in the epithelia of the zebrafish distal pronephric duct. While the former is characterized by at least 15 apically localized cilia and expresses centrin2 and rfx2, the latter is characterized by a single primary cilium and sodium pumps. Multi-cilia cells and principal cells differentiate from 17.5 hours post-fertilization onwards in a mosaic pattern. Jagged2a-Notch1a/Notch3-Her9 is responsible for specification and patterning of these two cell types through a lateral inhibition mechanism. Furthermore, multi-cilia cell hyperplasia was observed in mind bomb mutants and Mind bomb was shown to interact with Jagged2a and facilitate its internalization. Taken together, our findings add a new paradigm of Notch signaling in kidney development, namely, that Jagged2a-Notch signaling modulates cell fate choice in a nephric segment, the distal pronephric duct.
Highlights
In vertebrates, development of the excretory system is characterized by the successive formation of three distinct kidneys with increased complexity: pronephros, mesonephros, and metanephros
Two types of epithelial cells were found in the pronephric duct: multi-cilia cells and principal cells, which could be distinguished based on morphology and expression of different marker genes
Using existing zebrafish mutants and a knockdown technique, we demonstrated that the mosaic pattern and differentiation of these two cell types are controlled through a Notch-dependent lateral inhibition mechanism
Summary
Development of the excretory system is characterized by the successive formation of three distinct kidneys with increased complexity: pronephros, mesonephros, and metanephros. In the early life of fish and amphibians, the pronephros is a functional filtration organ that develops very to metanephros, and has been used as a model for kidney development. Though quite uniform in appearance, the tubule and duct epithelia are further subdivided into distinct segments, recognized by the expression of specific membrane transporters [4]. This is a general feature of vertebrate kidneys, where osmoregulatory function depends on an organized disposition of different transporters operating sequentially along the nephron [5,6,7]
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