Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

Ranjula Wijayatunge, Sam R. Holmstrom, Samantha B. Foley, Victoria E. Mgbemena, Varsha Bhargava, Gerardo Lopez Perez, Kelly McCrum, Theodora S Ross

Research output: Contribution to journalArticle

Abstract

Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.

Original languageEnglish (US)
JournalMolecular and Cellular Biology
Volume38
Issue number23
DOIs
StatePublished - Dec 1 2018

Fingerprint

Protein Deficiency
Phosphorylcholine
Phenotype
Proteins
Choline
glycerophosphodiester phosphodiesterase
Huntingtin Protein
Metabolomics
Knockout Mice
Germ Cells
Introns
Down-Regulation
Spleen
Complementary DNA
Alleles
Kidney
Gene Expression

Keywords

  • Cre recombinase
  • endocytosis
  • GDE7
  • GDPD3
  • HIP1
  • kypholordosis
  • phosphocholine

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis. / Wijayatunge, Ranjula; Holmstrom, Sam R.; Foley, Samantha B.; Mgbemena, Victoria E.; Bhargava, Varsha; Perez, Gerardo Lopez; McCrum, Kelly; Ross, Theodora S.

In: Molecular and Cellular Biology, Vol. 38, No. 23, 01.12.2018.

Research output: Contribution to journalArticle

Wijayatunge, Ranjula ; Holmstrom, Sam R. ; Foley, Samantha B. ; Mgbemena, Victoria E. ; Bhargava, Varsha ; Perez, Gerardo Lopez ; McCrum, Kelly ; Ross, Theodora S. / Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis. In: Molecular and Cellular Biology. 2018 ; Vol. 38, No. 23.
@article{329bb3bb7652496d8a31f7bcfbbda5cc,
title = "Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis",
abstract = "Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.",
keywords = "Cre recombinase, endocytosis, GDE7, GDPD3, HIP1, kypholordosis, phosphocholine",
author = "Ranjula Wijayatunge and Holmstrom, {Sam R.} and Foley, {Samantha B.} and Mgbemena, {Victoria E.} and Varsha Bhargava and Perez, {Gerardo Lopez} and Kelly McCrum and Ross, {Theodora S}",
year = "2018",
month = "12",
day = "1",
doi = "10.1128/MCB.00385-18",
language = "English (US)",
volume = "38",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "23",

}

TY - JOUR

T1 - Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression, Low Phosphocholine, and Kypholordosis

AU - Wijayatunge, Ranjula

AU - Holmstrom, Sam R.

AU - Foley, Samantha B.

AU - Mgbemena, Victoria E.

AU - Bhargava, Varsha

AU - Perez, Gerardo Lopez

AU - McCrum, Kelly

AU - Ross, Theodora S

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.

AB - Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.

KW - Cre recombinase

KW - endocytosis

KW - GDE7

KW - GDPD3

KW - HIP1

KW - kypholordosis

KW - phosphocholine

UR - http://www.scopus.com/inward/record.url?scp=85056504958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056504958&partnerID=8YFLogxK

U2 - 10.1128/MCB.00385-18

DO - 10.1128/MCB.00385-18

M3 - Article

VL - 38

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 23

ER -