Quantitative Genetic Analysis of Ventral Midbrain and Liver Iron in BXD Recombinant Inbred Mice

Jones, Byron C.; Reed, Cheryl; Hitzemann, Robert; Wiesinger, Jason A.; McCarthy, K; Buwen, James P.; Beard, John L.

doi:10.1080/10284150310001624192

Cited by 43 publications

(56 citation statements)

References 39 publications

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“…4 A and B). Interestingly, a prior analysis has revealed that these (and other) DA-related phenotypes are associated with midbrain iron levels (25). Consistent with these findings, the GK mSERT haplotype associates significantly with elevated iron levels in both the region of DA cell bodies (ventral midbrain) and DA terminal fields (caudateputamen) (Fig.…”

Section: In Silico Identification Of Phenotypes Influenced By Slc6a4 supporting

confidence: 75%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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Section: In Silico Identification Of Phenotypes Influenced By Slc6a4 supporting

confidence: 75%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…This is an intriguing QTL as the DAT is one of the main targets for psychostimulant action. Another QTL potentially related to dopamine system function, Vmbic10 (ventral midbrain iron content) also maps at 24 cM on Chr 11 (Jones et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative trait analysis, using panels of BxD recombinant inbred (RI) mice, continues to be one of the leading methods for the study of genes involved in complex neurobehavioral traits. The BxD series has been used to nominate and map QTL that contribute to a wide variety of complex traits including behavioral, pharmacological, neurochemical and neuroanatomical phenotypes (Erwin et al, 1997;Garlow et al, 2005Garlow et al, , 2006Jones et al, 1999Jones et al, , 2003Gora-Masalak et al, 1991;Belknap et al, 1992;Zhang and Gershenfeld 2003). The major goal of this study is to conduct quantitative trait analysis of CART expression in hypothalamus, by utilizing the BxD series of RI mice.…”

Section: Introductionmentioning

confidence: 99%

Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice

Boone

Hawks

et al. 2008

Brain Research

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Cocaine-Amphetamine Regulated Transcript (CART) peptides are implicated in a wide range of behaviors including in the reinforcing properties of psychostimulants, feeding and energy balance and stress and anxiety responses. We conducted a complex trait analysis to examine natural variation in the regulation of CART transcript abundance (CARTta) in the hypothalamus. CART transcript abundance was measured in total hypothalamic RNA from 26 BxD recombinant inbred (RI) mouse strains and in the C57BL/6 (B6) and DBA/2J (D2) progenitor strains. The strain distribution pattern for CARTta was continuous across the RI panel, which is consistent with this being a quantitative trait. Marker regression and interval mapping revealed significant quantitative trait loci (QTL) on mouse chromosome 4 (around 58.2cM) and chromosome 11 (between 20-36cM) that influence CARTta and account for 31% of the between strain variance in this phenotype. There are numerous candidate genes and QTL in these chromosomal regions that may indicate shared genetic regulation between CART expression and other neurobiological processes referable to known actions of this neuropeptide.

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“…Fe, Cu, and Zn in the brain are of widespread neurobiological importance as they contribute to a diverse set of biochemical processes, including energy metabolism (Fe, Cu), antioxidant defense (Cu, Zn), myelination (Fe), DNA synthesis (Fe, Zn), and neurotransmitter synthesis (Fe, Cu) (Linder and Hazegh-Azam, 1996;Beard, 2003;Frederickson et al, 2005). Deficiencies of these metals are thus detrimental to brain function; yet, they must be regulated strictly because they are toxic when in excess (Levenson, 2005).…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

2008

Self Cite

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Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.

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Quantitative Genetic Analysis of Ventral Midbrain and Liver Iron in BXD Recombinant Inbred Mice

Cited by 43 publications

References 39 publications

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice

Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

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