Developmental Programming of Branching Morphogenesis in the Kidney

Abstract

The kidney developmental program encodes the intricate branching and organization of approximately 1 million functional units (nephrons). Branching regulation is poorly understood, as is the source of a 10-fold variation in nephron number. Notably, low nephron count increases the risk for developing hypertension and renal failure. To better understand the source of this variation, we analyzed the complete gestational trajectory of mouse kidney development. We constructed a computerized architectural map of the branching process throughout fetal life and found that organogenesis is composed of two distinct developmental phases, each with stage-specific rate and morphologic parameters. The early phase is characterized by a rapid acceleration in branching rate and by branching divisions that repeat with relatively reproducible morphology. The latter phase, however, is notable for a significantly decreased yet constant branching rate and the presence of nonstereotyped branching events that generate progressive variability in tree morphology until birth. Our map identifies and quantitates the contribution of four developmental mechanisms that guide organogenesis: growth, patterning, branching rate, and nephron induction. When applied to organs that developed under conditions of malnutrition or in the setting of growth factor mutation, our normative map provided an essential link between kidney architecture and the fundamental morphogenetic mechanisms that guide development. This morphogenetic map is expected to find widespread applications and help identify modifiable targets to prevent developmental programming of common diseases.

Statistical theory of branching morphogenesis

“…Once again, comparison of the ductal network statistics obtained from measurements made during embryonic development with numerical simulations generated from the branching-annihilating random walk paradigm showed remarkably good agreement over a range of developmental time points . In particular, the data indicated that, although branching was seemingly stereotypic early in development, with most tips belonging to similar generations, this changed markedly post E15.5 (Sampogna et al, 2015), with considerable widening of the tip generation numbers, consistent with the predictions of the model. Quantitatively, by adjusting the two parameters of the theory -the ratio of the branching and elongation rates, and the contact radius of tip annihilation, good quantitative agreement was found for the variation of termination probability with branch index, as well as the distribution of branch number, subtree size and subtree persistence across a range of developmental time points.…”

“…Interestingly, tip arrest in these explants was shown to be dependent on Bmp7, a member of the TGFβ super‐family (Davies et al., ), which hints that the core findings from mammary gland could be translatable in other organs. Therefore, based on published data on the detailed structure of three‐dimensional kidney morphogenesis in vivo (Sampogna, Schneider, & Al‐Awqati, ), the question of whether there is a statistical basis to the branching network topology was addressed (Hannezo et al., ). Notably, in the three‐dimensional system, as well as the measured ratio of ductal elongation to branching rates, a second parameter had to be considered – the contact distance within which active tips become terminated against maturing ducts.…”

“…Frustratingly, around E15, when differences in model predictions would begin to impact, the two different experimental datasets yield different levels of branching heterogeneity, a discrepancy that will need to be resolved. However, branching data from later time points (E15.5–E19.5, Sampogna et al., ) reveals a dramatic widening of the subtree size distributions and tip generation numbers, which can be well‐fit by the branching‐annihilating random walk paradigm (Hannezo et al., ). This contrasts with a model based on deterministic tip delay, which would predict that all tips should have comparable generation numbers (within a small variance of three to four generations).…”

4D Biofabrication of Branching Multicellular Structures: A Morphogenesis Simulation Based on Turing’s Reaction-Diffusion Dynamics

“…The branching occur in sequence: first, side branching creates the primary stalks; then, there is a change of mode to tip splitting. The kidney developmental program encodes the intricate branching and organization of approximately 1 million functional units (nephrons) [9]. These phenomena have been hypothesized to be under genetic controls [7,10,11].…”

Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney

“…Serum deprivation, which is used to mimic malnutrition, was found to down-regulate the spontaneous calcium activity and to retard nephron formation. In the current study, we have characterized this spontaneous calcium activity using kidneys derived from 14-d-old rat embryos (9). After having identified the endoplasmic reticulum (ER) as the major source of spontaneous calcium signals in the embryonic rat kidney, we examined how those signals contribute to regulation of branching morphogenesis during embryonic kidney development.…”