Abstract
Branching morphogenesis is a crucial part of early developmental processes in diverse organs, but the detailed mechanism of this morphogenic event remains to be elucidated. Here we introduce an unknown mechanism leading to branching morphogenesis using mouse embryonic organotypic cultures with time-lapse live imaging. We found spatially expressed L-type voltage-dependent Ca2+ channels (VDCCs) in the peripheral layers of developing epithelial buds and identified the VDCCs as a core signaling mediator for patterning branching architecture. In this process, differential growth in peripheral layers by VDCC-induced ERK activity promoted cleft formation through an epithelial buckling-folding mechanism. Our findings reveal an unexpected role of VDCCs in developmental processes, and address a fundamental question regarding the initial process of branching morphogenesis.
Highlights
Branching morphogenesis is an essential developmental process in early organogenesis of diverse organs such as the lungs, kidneys, and many types of glands[1]
Among the molecules related to [Ca2+]o transport, we identified that several types of voltage-dependent Ca2+ channels (VDCCs), transient receptor potential (TRP) channels, and stromal interaction molecule (STIM) 1 are highly expressed in the critical period for branching organization [embryonic day (E) 12–16]
How can VDCC–extracellular signal-related kinase (ERK) signals trigger the branching process? We focused on the concept of differential growth, in which localized proliferation organizes epithelial architecture during the initial developmental process[25]
Summary
Branching morphogenesis is an essential developmental process in early organogenesis of diverse organs such as the lungs, kidneys, and many types of glands[1]. Branching morphogenesis increases material transport efficiency by expanding the surface area within the confined organ space, and organizes the organ primordia into a functional complex through reciprocal interactions between the epithelium and surrounding mesenchyme[2,3] In this process, the epithelial bud presents a characteristic morphological pattern depending on the organ type though there is a largely shared developing mechanism. VDCCs regulate a variety of cellular events, such as actomyosin contraction, synaptic transmission, and hormonal secretion according to the interacting partners with entered Ca2+ 10 In addition to these canonical functions, VDCCs are involved in the other cellular functions including cell motility, front-rear polarity, and immune response, which are mainly studied in non-excitable cell types[11,12,13]. Establishes differential growth patterns in developing epithelial buds, resulting in the spatial rearrangement of branching structures
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