CyFIP1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice

Dependence on CYFIP2 genetic background, parent-of origin, and sex

Richard K. Babbs, Jacob A. Beierle, Qiu T. Ruan, Julia C. Kelliher, Melanie M. Chen, Ashley X. Feng, Stacey L. Kirkpatrick, Fabiola A. Benitez, Fred A. Rodriguez, Johanne J. Pierre, Jeya Anandakumar, Vivek Kumar, Megan Mulligan, Camron D. Bryant

Research output: Contribution to journalArticle

Abstract

Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/- has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1+/- mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.

Original languageEnglish (US)
Pages (from-to)3009-3022
Number of pages14
JournalG3: Genes, Genomes, Genetics
Volume9
Issue number9
DOIs
StatePublished - Sep 1 2019

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Compulsive Behavior
Haploinsufficiency
Bulimia
Eating
Prader-Willi Syndrome
Proteins
Mothers
Obsessive Behavior
Food
Hyperphagia
Nucleus Accumbens
Hypothalamus
Obesity
Genetic Background
Phenotype
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

CyFIP1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice : Dependence on CYFIP2 genetic background, parent-of origin, and sex. / Babbs, Richard K.; Beierle, Jacob A.; Ruan, Qiu T.; Kelliher, Julia C.; Chen, Melanie M.; Feng, Ashley X.; Kirkpatrick, Stacey L.; Benitez, Fabiola A.; Rodriguez, Fred A.; Pierre, Johanne J.; Anandakumar, Jeya; Kumar, Vivek; Mulligan, Megan; Bryant, Camron D.

In: G3: Genes, Genomes, Genetics, Vol. 9, No. 9, 01.09.2019, p. 3009-3022.

Research output: Contribution to journalArticle

Babbs, RK, Beierle, JA, Ruan, QT, Kelliher, JC, Chen, MM, Feng, AX, Kirkpatrick, SL, Benitez, FA, Rodriguez, FA, Pierre, JJ, Anandakumar, J, Kumar, V, Mulligan, M & Bryant, CD 2019, 'CyFIP1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice: Dependence on CYFIP2 genetic background, parent-of origin, and sex', G3: Genes, Genomes, Genetics, vol. 9, no. 9, pp. 3009-3022. https://doi.org/10.1534/g3.119.400470
Babbs, Richard K. ; Beierle, Jacob A. ; Ruan, Qiu T. ; Kelliher, Julia C. ; Chen, Melanie M. ; Feng, Ashley X. ; Kirkpatrick, Stacey L. ; Benitez, Fabiola A. ; Rodriguez, Fred A. ; Pierre, Johanne J. ; Anandakumar, Jeya ; Kumar, Vivek ; Mulligan, Megan ; Bryant, Camron D. / CyFIP1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice : Dependence on CYFIP2 genetic background, parent-of origin, and sex. In: G3: Genes, Genomes, Genetics. 2019 ; Vol. 9, No. 9. pp. 3009-3022.
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abstract = "Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70{\%} of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/- has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1+/- mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.",
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T1 - CyFIP1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice

T2 - Dependence on CYFIP2 genetic background, parent-of origin, and sex

AU - Babbs, Richard K.

AU - Beierle, Jacob A.

AU - Ruan, Qiu T.

AU - Kelliher, Julia C.

AU - Chen, Melanie M.

AU - Feng, Ashley X.

AU - Kirkpatrick, Stacey L.

AU - Benitez, Fabiola A.

AU - Rodriguez, Fred A.

AU - Pierre, Johanne J.

AU - Anandakumar, Jeya

AU - Kumar, Vivek

AU - Mulligan, Megan

AU - Bryant, Camron D.

PY - 2019/9/1

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N2 - Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/- has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1+/- mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.

AB - Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/- has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1+/- mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.

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