Situs inversus in Dpcd/Poll-/-, Nme7-/- , and Pkd1l1-/- mice.
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.
Vogel
P
P
Pathology Department, Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA. pvogel@lexpharma.com
Read
R
R
Hansen
G M
GM
Freay
L C
LC
Zambrowicz
B P
BP
Sands
A T
AT
D000818:Animals; D002923:Cilia / Q000235:genetics; D002925:Ciliary Motility Disorders / Q000235:genetics / Q000662:veterinary; D019951:DNA Polymerase beta / Q000235:genetics*; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice / Q000002:abnormalities / Q000235:genetics; D018345:Mice, Knockout / Q000002:abnormalities / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012376:Rodent Diseases / Q000235:genetics*; D012857:Situs Inversus / Q000235:genetics / Q000662:veterinary*
D008565:Membrane Proteins; C486742:Pkd1l1 protein, mouse; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta