Molecular insights into segmentation along the proximal-distal axis of the nephron - PubMed (original) (raw)

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Molecular insights into segmentation along the proximal-distal axis of the nephron

Raphael Kopan et al. J Am Soc Nephrol. 2007 Jul.

Abstract

The structure of a mammalian kidney is parsed into large collections of polarized nephrons, and each segment is home to a diverse community of cells that specialize in renal endocrine and excretory functions. Early developmental lengthening and diversification of nephron segments along a proximal--distal axis initiate all subsequent facets of tubular growth and function. Morphogenic cues and biochemical interactions that are critical to this process are starting to emerge. The underlying principles of regional cell signaling and transcriptional control organizing early segmentation are the subject of this review.

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Figures

Figure 1

Figure 1. Schematic summary of expected and observed results from genetic manipulation of the metanephros

A. Wild type renal vesicle acquires a proximal identity first and has a stereotypical position relative to the ureteric bud. B. Without Wnt9b, no renal vesicle develops. C-F. Although a greater sample needs to be analyzed, Six2-/- mice permit discrimination between several mechanistic possibilities. Hypothetically, in the absence of Six2, all metanephric mesenchyme cells could respond to Wnt9b and convert to an epithelial structure (C; Six2-/-1), but in reality, only a subset form ectopic renal vesicle with regular spacing between them (D; Six2-/-2). In addition, the distal ends of the ectopic vesicles are almost always closer to the ureteric bud, suggesting that a signal from the ureteric bud polarizes the vesicles along the proximal/distal axis. E. In theory, if a global patterning cue existed, all ectopic renal vesicles should align to the field (as in Six2-/-3) but this is not the case in the Six2-/- metanephros. F. Another possibility is that only the proximal ureteric bud organizes the renal vesicle along the proximal-distal axis, or the proximal-distal segmentation program is an intrinsic renal vesicle property that does not require external cues. In both these cases randomized proximal-distal acquisition is expected (Six2-/-4). G-I. Polarization defects in Lhx1, Notch2 and NICD1 mutants. Note that over-expression of activated Notch1 differs from loss of Six2 in that it results in multiple, poorly spaced epithelial clusters.

Figure 2

Figure 2. A model for the molecular circuitry involved in segmenting the nephron

Pax2, Lhx1, and Brn1 are involved in establishing the distal segment; Notch2 is required to fix the proximal identities and to establish proximal precursors. MM—metanephric mesenchyme; UB— ureteric bud; and CB and SB—Comma and S-shaped bodies. See text for details.

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