Dataset Information

A full lifespan model of vertebrate lens growth.

ABSTRACT: The mathematical determinants of vertebrate organ growth have yet to be elucidated fully. Here, we utilized empirical measurements and a dynamic branching process-based model to examine the growth of a simple organ system, the mouse lens, from E14.5 until the end of life. Our stochastic model used difference equations to model immigration and emigration between zones of the lens epithelium and included some deterministic elements, such as cellular footprint area. We found that the epithelial cell cycle was shortened significantly in the embryo, facilitating the rapid growth that marks early lens development. As development progressed, epithelial cell division becomes non-uniform and four zones, each with a characteristic proliferation rate, could be discerned. Adjustment of two model parameters, proliferation rate and rate of change in cellular footprint area, was sufficient to specify all growth trajectories. Modelling suggested that the direction of cellular migration across zonal boundaries was sensitive to footprint area, a phenomenon that may isolate specific cell populations. Model runs consisted of more than 1000 iterations, in each of which the stochastic behaviour of thousands of cells was followed. Nevertheless, sequential runs were almost superimposable. This remarkable degree of precision was attributed, in part, to the presence of non-mitotic flanking regions, which constituted a path by which epithelial cells could escape the growth process. Spatial modelling suggested that clonal clusters of about 50 cells are produced during migration and that transit times lengthen significantly at later stages, findings with implications for the formation of certain types of cataract.

SUBMITTER: Sikic H

PROVIDER: S-EPMC5319337 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A full lifespan model of vertebrate lens growth.

Šikić Hrvoje H Shi Yanrong Y Lubura Snježana S Bassnett Steven S

Royal Society open science 20170118 1

The mathematical determinants of vertebrate organ growth have yet to be elucidated fully. Here, we utilized empirical measurements and a dynamic branching process-based model to examine the growth of a simple organ system, the mouse lens, from E14.5 until the end of life. Our stochastic model used difference equations to model immigration and emigration between zones of the lens epithelium and included some deterministic elements, such as cellular footprint area. We found that the epithelial cel ...[more]

PMID: 28280571

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Project description:Xenopus laevis is among the few species that are capable of fully regenerating a lost lens de novo. This occurs upon removal of the lens, when secreted factors from the retina are permitted to reach the cornea epithelium and trigger it to form a new lens. Although many studies have investigated the retinal factors that initiate lens regeneration, relatively little is known about what factors support this process and make the cornea competent to form a lens. We presently investigate the role of Retinoic acid (RA) signaling in lens regeneration in Xenopus. RA is a highly important morphogen during vertebrate development, including the development of various eye tissues, and has been previously implicated in several regenerative processes as well. For instance, Wolffian lens regeneration in the newt requires active RA signaling. In contrast, we provide evidence here that lens regeneration in Xenopus actually depends on the attenuation of RA signaling, which is regulated by the RA-degrading enzyme CYP26. Using RT-PCR we examined the expression of RA synthesis and metabolism related genes within ocular tissues. We found expression of aldh1a1, aldh1a2, and aldh1a3, as well as cyp26a1 and cyp26b1 in both normal and regenerating corneal tissue. On the other hand, cyp26c1 does not appear to be expressed in either control or regenerating corneas, but it is expressed in the lens. Additionally in the lens, we found expression of aldh1a1 and aldh1a2, but not aldh1a3. Using an inhibitor of CYP26, and separately using exogenous retinoids, as well as RA signaling inhibitors, we demonstrate that CYP26 activity is necessary for lens regeneration to occur. We also find using phosphorylated Histone H3 labeling that CYP26 antagonism reduces cell proliferation in the cornea, and using qPCR we find that exogenous retinoids alter the expression of putative corneal stem cell markers. Furthermore, the Xenopus cornea is composed of an outer layer and inner basal epithelium, as well as a deeper fibrillar layer sparsely populated with cells. We employed antibody staining to visualize the localization of CYP26A, CYP26B, and RALDH1 within these corneal layers. Immunohistochemical staining of these enzymes revealed that all 3 proteins are expressed in both the outer and basal layers. CYP26A appears to be unique in also being present in the deeper fibrillar layer, which may contain cornea stem cells. This study reveals a clear molecular difference between newt and Xenopus lens regeneration, and it implicates CYP26 in the latter regenerative process.

Dataset Information

A full lifespan model of vertebrate lens growth.

Publications

A full lifespan model of vertebrate lens growth.

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