Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner

Hohoff, Christa; Zhang, Mingyue; Ambrée, Oliver; Kravchenko, Mykola; Buschert, Jens; Kerkenberg, Nicole; Gorinski, Nataliya; Galil, Dalia Abdel; Schettler, Christiane; Werth, Kari Lavinia vom; Wewer, Maximilian; Schneider, Ilona; Grotegerd, Dominik; Wachsmuth, Lydia; Faber, Cornelius; Skryabin, Boris V.; Brosius, Juergen; Ponimaskin, Evgeni; Zhang, Weiqi

doi:10.1007/s00429-019-01898-6

Cited by 14 publications

(39 citation statements)

References 66 publications

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“…Palmitoylation is a posttranscriptional process in which a palmityl group is added to specific target amino acid sequences expressed by a protein, in this case, an ERα. Palmitoylation controls the trafficking, cellular compartment localization, and interaction of ERα with other proteins via association with membrane lipid rafts and similar structures such as caveolins (Adlanmerini et al, 2014; Anbalagan, Huderson, Murphy, & Rowan, 2012; Anderson & Ragan, 2016; Hohoff et al, 2019; Lathe & Houston, 2018; Meitzen et al, 2013; Meitzen, Britson, Tuomela, & Mermelstein, 2019; Pedram, Razandi, Deschenes, & Levin, 2012; Tonn Eisinger et al, 2018). In the striatum and hippocampus, palmitoylated ERα trigger signal transduction cascades from the neuronal plasma membrane through, at a minimum, activation of mGluRs (Boulware et al, 2005; Grove‐Strawser, Boulware, & Mermelstein, 2010; Miller, Krentzel, Patisaul, & Meitzen, 2019; Peterson, Mermelstein, & Meisel, 2015; Song, Yang, Peckham, & Becker, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…We also observed a sex‐specific time course for ERα nuclear expression where females showed more ERα‐IR cells as well as this nuclear expression persisted until P20 which did not in males. It is possible that sex differences in select DHHC or caveolin gene expression may underlie these differences, similar to the hippocampal regions (Hohoff et al, 2019; Meitzen et al, 2019; Meitzen, Luoma, et al, 2013b). Quantifying DHHC expression and activity across development will be necessary to test this hypothesis further.…”

Section: Discussionmentioning

confidence: 99%

“…The first model (Figure 9a) posits that striatal neurons express both nuclear and extranuclear ERα and GPER1 just after birth and that the transition into adulthood to exclusively extranuclear expression is accomplished by the disappearance of nuclear ERs. This disappearance would be medi- and similar structures such as caveolins (Adlanmerini et al, 2014;Anbalagan, Huderson, Murphy, & Rowan, 2012;Anderson & Ragan, 2016;Hohoff et al, 2019;Lathe & Houston, 2018;Meitzen, Britson, Tuomela, & Mermelstein, 2019;Pedram, Razandi, Deschenes, & Levin, 2012;Tonn Eisinger et al, 2018). In the striatum and hippocampus, palmitoylated ERα trigger signal transduction cascades from the neuronal plasma membrane through, at a minimum, activation of mGluRs (Boulware et al, 2005;Grove-Strawser, Boulware, & Mermelstein, 2010;Miller, Krentzel, Patisaul, & Meitzen, 2019;Peterson, Mermelstein, & Meisel, 2015;Song, Yang, Peckham, & Becker, 2019).…”

Section: Limitations To This Studymentioning

confidence: 99%

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Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

Krentzel

Willett

Johnson

et al. 2020

J of Comparative Neurology

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Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through differential production via the enzyme aromatase. ERs and aromatase are expressed across the nervous system, including in the striatal brain regions. These regions, comprising the nucleus accumbens core, shell, and caudate-putamen, are instrumental for a wide-range of functions and disorders that show sex differences in phenotype and/or incidence. Sex-specific estrogen action is an integral component for generating these sex differences. A distinctive feature of the striatal regions is that in adulthood neurons exclusively express membrane but not nuclear ERs. This long-standing finding dominates models of estrogen action in striatal regions. However, the developmental etiology of ER and aromatase cellular expression in female and male striatum is unknown. This omission in knowledge is important to address, as developmental stage influences cellular estrogenic mechanisms. Thus, ERα, GPER1, and aromatase cellular immunoreactivity was assessed in perinatal, prepubertal, and adult female and male rats. We tested the hypothesis that ERα, GPER1, and aromatase exhibits sex, region, and age-specific differences, including nuclear expression. ERα exhibits nuclear expression in all three striatal regions before adulthood and disappears in a region-and sex-specific time-course. Cellular GPER1 expression decreases during development in a region-but not sex-specific time-course, resulting in extranuclear expression by adulthood. Somatic aromatase expression presents at prepuberty and increases by adulthood in a region-but not sex-specific time-course. These data indicate that developmental period exerts critical sex-specific influences on striatal cellular estrogenic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Limitations To This Studymentioning

confidence: 99%

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Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

Krentzel

Willett

Johnson

et al. 2020

J of Comparative Neurology

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“…Zdhhc7 -/mice -To investigate the impact of DHHC7 on barttin palmitoylation in vivo, we established a Zdhhc7 -/mouse line (27). We previously demonstrated that Zdhhc7 -/mice possess a normal range of sensory and motor activity and reproduction.…”

Section: Characterization Of the Kidney Morphology Ofmentioning

confidence: 99%

“…Morphologic evaluation (Axioskop 40, Zeiss microscope) was performed by a trained pathologist and representative microphotographs were taken (AxioCam MRc, Zeiss). Low-salt diet experiment and blood measurements -For in vivo experiments, three months old male Zdhhc7 +/+ (WT) and Zdhhc7 -/-(KO) mice (27) were subjected to standard diet (Na 2181.580 mg/kg; Cl 3628.760 mg/kg; K 6961.760 mg/kg) or to low-salt diet (Na 130.590 mg/kg; Cl 113.548 mg/kg; K 7088,293 mg/kg) for 12 days with water ad libitum. Both diets were purchased from Altromin (Germany).…”

Section: Biochemical Analysis Of Clc-ka/barttin Surface Membrane Insementioning

confidence: 99%

DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels

Gorinski

Wojciechowski

Guseva

et al. 2020

Journal of Biological Chemistry

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Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this posttranslational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl-https://www.jbc.org/cgi/

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Acute stress reveals different impacts in male and female Zdhhc7-deficient mice

et al. 2021

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Numerous processes of neuronal development and synaptic plasticity in the brain rely on the palmitoyl acyltransferase ZDHHC7, as it palmitoylates various synaptic and extrasynaptic proteins such as neural cell adhesion molecule (NCAM) or gamma-aminobutyric acid (GABAA) receptors. In addition, ZDHHC7 palmitoylates sex steroid hormone receptors and is, therefore, indirectly linked to mental disorders that often occur because of or in conjunction with stress. In this work, we investigated how ZDHHC7 affects stress responses in mice. For this purpose, genetically modified mice with a knockout of the Zdhhc7 gene (KO) and wild-type (WT) littermates of both sexes were exposed to acute stressors or control conditions and examined with regard to their behavior, brain microstructure, gene expression, and synaptic plasticity. While no behavioral effects of acute stress were found, we did find that acute stress caused reduced mRNA levels of Esr1 and Esr2 coding for estrogen receptor α and β in the medial prefrontal cortex of male WT and KO mice. Strikingly, after acute stress only male KO mice showed reduced mean fiber lengths of the medioventral hippocampus. Furthermore, Zdhhc7-deficiency impaired synaptic plasticity in mice of both sexes, while acute stress improved it in females, but not in male mice. Taken together, our findings suggest that ZDHHC7 plays a modulatory role in the brain that leads to sex-specific stress responses, possibly due to estrogen receptor-mediated signaling pathways.

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Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner

Cited by 14 publications

References 66 publications

Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels

Acute stress reveals different impacts in male and female Zdhhc7-deficient mice

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