title: mdr1a deficiency corrects sterility in Niemann-Pick C1 protein deficient female mice.
abstract: Niemann-Pick type C disease is a progressive neurological disease with cholesterol storage in liver, and npc1-/- mice share these features and are sterile. We have searched for the cause of sterility and found normal folliculogenesis and progesterone levels but lack of implantation. Multiple drug resistance (MDR) P-glycoproteins are plasma membrane proteins implicated in the movement of drugs and lipids across membranes. Their functions are inhibited by progesterone, which has been shown to alter cellular cholesterol homeostasis and has implicated P-glycoproteins in the movement of cholesterol to the endoplasmic reticulum. We have introduced the mdr1a knockout into the npc1 mutant line. While the neurological disease continues at its usual rate, preventing the females from taking care of their litters, npc1-/-, mdr1a-/- females became fertile. Although the mdr1a P-glycoprotein co-localizes with caveolae, neither caveolin-1 nor npc1 levels were significantly altered in the livers of double homozygotes. The absence of mdr1a was confirmed by immunoblotting, but npc1 deficiency was not associated with consistent changes in cerebellar mdr1a in mdr1a+/+ mice. The results show that a mdr1a mutation is an in vivo suppressor of female sterility in npc1 deficient mice.
authors: Department of Pediatrics, Section of Medical and Molecular Genetics, Angel Charity for Children-Wings for Genetic Research, Steele Memorial Children's Research Center, Arizona, USA. erickson@peds.arizona.edu
authors: Robert P
authors: RP
authors: Erickson
authors: Monica
authors: M
authors: Kiela
authors: Patrick J
authors: PJ
authors: Devine
authors: Patricia B
authors: PB
authors: Hoyer
authors: Randall A
authors: RA
authors: Heidenreich
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D005260:Female; D007247:Infertility, Female / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D011374:Progesterone / Q000097:blood; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D011374:Progesterone; C095122:multidrug resistance protein 3