Incoherent collective cell chemotaxis underlies organ dysmorphia in a model of branchio-oto-renal syndrome

Abstract

Mutations in the transcriptional co-activator Eya1 cause branchio-oto-renal syndrome (BOR) in humans, and the equivalent conditions in vertebrates. BOR has an incidence of 1/40,000 and is characterized by congenital branchial fistulas, malformations of the inner ear and kidney hypoplasia. Therapeutic interventions for BOR are currently limited to reparative surgery, hearing aids and dialysis. Here we use the mechanosensory lateral line in zebrafish to better understand the role of Eya1 in organogenesis. The lateral line develops from a primordium formed by approximately 150 cells that move together from head to tail of the embryo at a constant velocity. This invariant migration occurs over a trail of Sdf1a chemokine and is controlled by the simultaneous action of two receptors. The CXCR4b is expressed in the front half of the primordium where it acts as a chemokine sensor, whereas the CXCR7b is present in the rear half, serving as a chemokine sink to ensure persistent directionality. We show that the loss of Eya1 strongly reduces the expression of CXCR7b, disrupting the coherent motion of the primordium and leading to lateral-line truncations. We also find evidence of reduced epithelial maturation in primordia lacking Eya1. These findings argue for abnormal collective cell chemotaxis as the origin of organ dysmorphia in BOR.