Planar differential growth rates determine the position of folds in complex epithelia

Abstract

Folding is a fundamental process shaping epithelial sheets into 3D architectures of organs. Initial positioning of folds is the foundation for the emergence of correct tissue morphology. Mechanisms forming individual folds have been studied, yet the precise positioning of the folds in complex, multifolded epithelia is an open question. We present a model of morphogenesis, encompassing local differential growth, and tissue mechanics to investigate tissue fold positioning. We use Drosophila melanogaster wing imaginal disc as our model system, and show that there is spatial and temporal heterogeneity in its planar growth rates. This planar differential growth is the main driver for positioning the folds. Increased stiffness of the apical layer and confinement by the basement membrane drive fold formation. These influence fold positions to a lesser degree. The model successfully predicts the emergent morphology of wingless spade mutant in vivo, via perturbations solely on planar differential growth rates in silico.

Growth control in the Drosophila wing disk

“…Further experiments are needed to define the mechanical interaction between the BM and columnar cells and to understand how feedback between the cells and the BM leads to coordinated growth. Several recent simulation studies have identified an important role for the BM and ECM in guiding fold formation in the growing wing disk (see Figure ), and in the overall mechanical properties of the wing disk (Atzeni, Lanfranconi, & Aegerter, ; Keller, Lanfranconi, & Aegerter, ; Tozluoğlu et al, ). How the basement membrane and ECM are temporally regulated to tune stress in the wing disk may have a profound effect on wing disk growth (Pastor‐Pareja & Xu, ).…”

Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix

“…Therefore, passive tension built up in the ECM (perhaps that is generated over time due to differential growth patterns) does not contribute significantly to shape generation, at least for the bent profile of the disc cross-section along the AP axis. Hence, our study suggest another possible mechanism which is different than differential growth hypothesis 39 to drive fold formation along the orthogonal dorsal-ventral axis. Perturbation studies that chemically dissolve collagen revealed that the ECM is essential to maintain the shape of the wing disc.…”

“…ECM remodeling follows the growth and division of epithelial cells in the wing disc 12 . A high growth rate of epithelial cells in comparison with ECM remodeling, can lead to accumulation of tensile stress in the ECM 39 . In other contexts, cell stresses are converted into pre-strains within the ECM 40 .…”

“…Very recent experimental results support a significant role of the ECM in maintaining the shape of the tissue. Keller et al demonstrated using finite element modeling and stretching experiments that the ECM is significantly stiffer than the columnar wing disc cells 39 . This provides additional evidence for compression by the ECM playing a defining role in maintaining the overall organ shape.…”

“…This provides additional evidence for compression by the ECM playing a defining role in maintaining the overall organ shape. In addition, Tozluoğlu et al showed that ECM plays a major role in maintaining the folds in the wing disc in the orthogonal dorsalventral direction 39 .…”