Situs Inversus in Dpcd/Poll–/–, Nme7–/–, and Pkd1l1–/– Mice

Abstract

Situs inversus (SI) is a congenital condition characterized by left–right transposition of thoracic and visceral organs and associated vasculature. The usual asymmetrical positioning of organs is established early in development in a transient structure called the embryonic node. The 2-cilia hypothesis proposes that 2 kinds of primary cilia in the embryonic node determine left–right asymmetry: motile cilia that generate a leftward fluid flow, and immotile mechanosensory cilia that respond to the flow. Here, we describe 3 mouse SI models that provide support for the 2-cilia hypothesis. In addition to having SI, Dpcd/Poll–/– mice (for: deleted in a mouse model of primary ciliary dyskinesia) and Nme7–/– mice (for: nonmetastatic cells 7) had lesions consistent with deficient ciliary motility: Hydrocephalus, sinusitis, and male infertility developed in Dpcd/Poll–/– mice, whereas hydrocephalus and excessive nasal exudates were seen in Nme7–/– mice. In contrast, the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1–/– mice (for: polycystic kidney disease 1 like 1) suggested that dysfunction of motile cilia was not involved in the development of SI in this line. Moreover, the gene Pkd1l1 has considerable sequence similarity with Pkd1 (for: polycystic kidney disease 1), which encodes a protein (polycystin-1) that is essential for the mechanosensory function of immotile primary cilia in the kidney. The markedly reduced viability of Pkd1l1–/– mice is somewhat surprising given the absence of any detected abnormalities (other than SI) in surviving Pkd1l1–/– mice subjected to a comprehensive battery of phenotype-screening exams. However, the heart and great vessels of Pkd1l1–/– mice were not examined, and it is possible that the decreased viability of Pkd1l1–/– mice is due to undiagnosed cardiovascular defects associated with heterotaxy.