Abstract
A notable example of spiral architecture in organs is the mammalian cochlear duct, where the morphology is critical for hearing function. Genetic studies have revealed necessary signaling molecules, but it remains unclear how cellular dynamics generate elongating, bending, and coiling of the cochlear duct. Here, we show that extracellular signal-regulated kinase (ERK) activation waves control collective cell migration during the murine cochlear duct development using deep tissue live-cell imaging, Förster resonance energy transfer (FRET)-based quantitation, and mathematical modeling. Long-term FRET imaging reveals that helical ERK activation propagates from the apex duct tip concomitant with the reverse multicellular flow on the lateral side of the developing cochlear duct, resulting in advection-based duct elongation. Moreover, model simulations, together with experiments, explain that the oscillatory wave trains of ERK activity and the cell flow are generated by mechanochemical feedback. Our findings propose a regulatory mechanism to coordinate the multicellular behaviors underlying the duct elongation during development.
Highlights
Spiral shapes are a widely occurring motif in many varied biological tissues and organisms, including shells, horns, and plants, but it has remained unclear how spiral shapes are formed spontaneously (Thompson, 1942)
The image domain of the cochlear duct was divided into interrogation regions and the averaged fluorescence intensity of labeled EdU was measured within each region
Previous genetic studies have revealed the molecular basis of cochlear duct elongation during development, but have been unable to explain the physical mechanisms by which the duct bends because of its severe phenotype (Bok et al, 2013; Groves and Fekete, 2012; Urness et al, 2018; Urness et al, 2015)
Summary
Spiral shapes are a widely occurring motif in many varied biological tissues and organisms, including shells, horns, and plants, but it has remained unclear how spiral shapes are formed spontaneously (Thompson, 1942). The cochlear duct, composed of epithelial cells, elongates, bends, and coils to form a spiral. Gene knockout studies have clarified that the elongation of the cochlear duct requires sonic hedgehog (SHH) signaling from the cochleovestibular ganglion in the conical central axis of the cochlea (Bok et al, 2013; Liu et al, 2010; Tateya et al, 2013), fibroblast growth factor (FGF) signaling of epithelial cells (Pauley et al, 2003; Pirvola et al, 2000; Urness et al, 2018; Urness et al, 2015), and non-
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