title: Huntingtin interacting proteins 14 and 14-like are required for chorioallantoic fusion during early placental development.
abstract: Huntington disease (HD) is an adult-onset neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms that is caused by a CAG expansion in the HTT gene. Palmitoylation is the addition of saturated fatty acids to proteins by DHHC palmitoylacyl transferases. HTT is palmitoylated by huntingtin interacting proteins 14 and 14-like (HIP14 and HIP14L or ZDHHC17 and 13 respectively). Mutant HTT is less palmitoylated and this reduction of palmitoylation accelerates its aggregation and increases cellular toxicity. Mouse models deficient in either Hip14 (Hip14(-/-)) or Hip14l (Hip14l(-/-)) develop HD-like phenotypes. The biological function of HTT palmitoylation and the role that loss of HTT palmitoylation plays in the pathogenesis of HD are unknown. To address these questions mice deficient for both genes were created. Loss of Hip14 and Hip14l leads to early embryonic lethality at day embryonic day 10-11 due to failed chorioallantoic fusion. The chorion is thickened and disorganized and the allantois does not fuse correctly with the chorion and forms a balloon-like shape compared to Hip14l(-/-); Hip14(+/+) littermate control embryos. Interestingly, the Hip14(-/-) ; Hip14(-/-) embryos share many features with the Htt(-/-) embryos, including folding of the yolk sac, a bulb shaped allantois, and a thickened and disorganized chorion. This may be due to a decrease in HTT palmitoylation. In Hip14(-/-); Hip14l(-/-) mouse embryonic fibroblasts show a 25% decrease in HTT palmitoylation compared to wild type cells. This is the first description of a double PAT deficient mouse model where loss of a PAT or multiple PATs results in embryonic lethality in mammals. These results reinforce the physiological importance of palmitoylation during embryogenesis.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, 950 28th Avenue West, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Shaun S
authors.initials: SS
authors.lastname: Sanders
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 10th Ave West, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Juan
authors.initials: J
authors.lastname: Hou
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, 950 28th Avenue West, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Liza M
authors.initials: LM
authors.lastname: Sutton
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 10th Ave West, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Garside
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, 950 28th Avenue West, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Katherine K N
authors.initials: KK
authors.lastname: Mui
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, 950 28th Avenue West, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, 950 28th Avenue West, Vancouver, British Columbia, Canada V5Z 4H4. Electronic address: mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 10th Ave West, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D049033:Chorioallantoic Membrane / Q000196:embryology*; D005260:Female; D005838:Genotype; D017403:In Situ Hybridization; D054878:Lipoylation; D008561:Membrane Fusion / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000196:embryology*; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D000217:Acyltransferases; C552301:Zdhhc13 protein, mouse; C569387:Zdhhc17 protein, mouse
keywords: Chorioallantoic fusion; HIP14 or ZDHHC17; HIP14L or ZDHHC13; Huntington disease; Palmitoylation; Placenta