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Background: Specification of the metanephric mesenchyme is a central step of kidney development as this mesenchyme promotes nephric duct induction to form a ureteric bud near its caudal end. Before ureteric bud formation, the caudal nephric duct swells to form a pseudostratified epithelial domain that later emerges as the tip of the bud. However, the signals that promote the formation of the transient epithelial domain remain unclear. Here, we investigated the early roles of the mesenchymal factor Six family and its cofactor Eya on the initial induction of nephric duct development. Results: The nephrogenic progenitor population is initially present but significantly reduced in mice lacking both Six1 and Six4 and undertakes an abnormal cell death pathway to be completely eliminated by ∼E10.5–E11.0, similar to that observed in Eya1-/- embryos. Consequently, the nephric duct fails to be induced to undergo normal proliferation to pseudostratify and form the ureteric bud in Six1-/-;Six4-/- or Eya1-/- embryos. Conclusions: Our data support a model where Eya-Six may form a complex to regulate nephron progenitor cell development before metanephric specification and are critical mesenchymal factors for inducing nephric duct development. Developmental Dynamics 244:866–873, 2015. © 2015 Wiley Periodicals, Inc.

Summary. The development and degeneration of the mesonephros of the sheep is described with particular reference to the curious glomerular structure occupying the cranial one-third of the organ and here referred to as the giant glomerulus. The giant glomerulus and in particular the cranial two tubules draining it on either side provide useful landmarks whereby corresponding regions may be compared at different ages. An attempt is made to analyse the factors which determine the form and relations of the definitive glomeruli and tubules. These factors include the early relations of the somitic stalks and nephrogenic cord, the precocity of growth and vascularization of the preglomerular tissue and the degree of overcrowding and overlapping of the tubule primordia. The cellular activities of the mesonephric tubules are described and discussed and the view is upheld that these are of a peculiar secretory nature. The processes occurring in degeneration are outlined and the absence of the massive cranial degeneration described by Felix in man is commented upon.

Embryonic mouse kidney mesenchymes of various ages were tested for their abilities to initiate and supportureteric bud morphogenesis in vitro. Nephrogenic cord mesenchyme taken from animals before metanephros initiation (10 days) was combined with ureteric buds. The buds showed no morphogenesis. This was true for presumptive metanephric mesenchyme and for mesenchymes (pronephric and mesonephric) already undergoing nephrogenesis. These results indicate basic physiological differences between pronephric, mesonephric and metanephric regions of the cord. When entire nephric systems were cultured alone no metanephros developed. This, and the fact that presumptive metanephric mesenchyme had no influence on ureteric buds, indicates that metanephros initiation (both bud and mesenchyme) results from some activity originating outside the nephrogenic cord. When combined with metanephric mesenchyme at various stages of tubulogenesis (loose, condensed, or tubular), ureteric buds branched only in the presence of the loose mesenchyme. Branching occurred in loose mesenchyme taken from 11 to 15 day kidneys. Apparently once a given group of cells begins tubulogenesis they lose their ability to induce ureteric bud morphogenesis. As tubulogenesis proceeds, the amount of loose mesenchymes per kidney decreases sharply. Ultimate size of the metanephros may be established by depletion of loose mesenchyme resulting in its ureteric bud-inducing potential falling below some critical level.