Caudal migration and proliferation of renal progenitors regulates early nephron segment size in zebrafish.

Richard W Naylor,Rachel C Dodd,Alan J Davidson

doi:10.1038/srep35647

Abstract

The nephron is the functional unit of the kidney and is divided into distinct proximal and distal segments. The factors determining nephron segment size are not fully understood. In zebrafish, the embryonic kidney has long been thought to differentiate in situ into two proximal tubule segments and two distal tubule segments (distal early; DE, and distal late; DL) with little involvement of cell movement. Here, we overturn this notion by performing lineage-labelling experiments that reveal extensive caudal movement of the proximal and DE segments and a concomitant compaction of the DL segment as it fuses with the cloaca. Laser-mediated severing of the tubule, such that the DE and DL are disconnected or that the DL and cloaca do not fuse, results in a reduction in tubule cell proliferation and significantly shortens the DE segment while the caudal movement of the DL is unaffected. These results suggest that the DL mechanically pulls the more proximal segments, thereby driving both their caudal extension and their proliferation. Together, these data provide new insights into early nephron morphogenesis and demonstrate the importance of cell movement and proliferation in determining initial nephron segment size.

Highlights

The mecom gene initially has an anterior expression boundary level with somite 6–7 but this gradually contracts until it is level with somite 14 at the 24 hours post-fertilization stage[13]
Considerable evidence indicates that the patterning of the intermediate mesoderm into rostral and caudal subdomains occurs in response to retinoic acid (RA) signalling
We find that the intermediate mesoderm, rather than being a relatively static stripe of cells that differentiates in situ, shows dynamic cellular movements and active proliferation

Summary

Introduction

The mecom gene initially has an anterior expression boundary level with somite 6–7 but this gradually contracts until it is level with somite 14 at the 24 hours post-fertilization (hpf) stage[13]. Zebrafish mutants defective in RA synthesis, or embryos treated with inhibitors of RA signalling, show a loss or reduction in the size of the rostral subdomain and a concomitant expansion in the size of the caudal subdomain[1,2,10,14] These changes are associated with altered proximo-distal patterning of the tubule segments at later stages, as read-out by segment-specific transporter genes, with RA-deficient embryos showing reduced or absent proximal segments and expanded distal segments. DL progenitors are found to move caudally towards the cloaca and in doing so, the other tubule segments are ‘pulled’ down the embryo This tensile force was found to influence the size of the DE segment, most likely via a mechanism involving stretch-activated proliferation

Methods

Results

Conclusion