Genetic analysis of attractin homologs

Walker, Will P.; Aradhya, Swaroop; Hu, Changbing; Shen, Shuai; Zhang, Wei; Azarani, Arezou; Lü, Xin; Barsh, Gregory S.; Gunn, Teresa M.

doi:10.1002/dvg.20351

Cited by 17 publications

(17 citation statements)

References 29 publications

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“…The Alp binding motif in Mc4r contains a putative phosphorylation site indicating that Alp might play a role in Mc4r trafficking. Alp knock-out mice appear normal with no alterations in body weight or pigmentation [51]. Further experiments using double mutants over-expressing Agrp and deficient for ALP could elucidate possible interaction of these two proteins in vivo.…”

Section: Mouse Models With Mutations In the Melanocortin Systemmentioning

confidence: 98%

Mouse models for the central melanocortin system

Bolze

Klingenspor

2009

Genes Nutr

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Obesity is characterized by an excess storage of body fat and promotes the risk for complex disease traits such as diabetes mellitus and cardiovascular diseases. The obesity prevalence in Europe is rising and meanwhile ranges from 10 to 20% in men and 15-25% in women. Body fat accumulation occurs in states of positive energy balance and is favored by interactions among environmental, psychosocial and genetic factors. Energy balance is regulated by a complex neuronal network of anorexigenic and orexigenic neurons which integrates peripheral and central hormonal and neuronal signals relaying information on the metabolic status of organs and tissues in the body. A key component of this network is the central melanocortin pathway in the hypothalamus that elicits metabolic and behavioral adaptations for the maintenance of energy homeostasis. Genetic defects in this system cause obesity in mice and humans. In this review we emphasize mouse models with spontaneous natural mutations as well as targeted mutations that contributed to our understanding of the central melanocortin system function in the control of energy balance.Keywords Energy balance Á Melanocortin Á Mouse models Á Obesity ObesityObesity is characterized by an excess of body fat and promotes the risk for the development of complex disease traits like diabetes mellitus, cardiovascular dysfunctions, certain forms of cancer and sleep-breathing disorders. World Health Organization defines obesity by a body mass index (BMI) larger than 30 kg/m 2 , whereas overweight is defined by a BMI between 25 and 29.9 kg/m 2 . The obesity prevalence in Europe ranges from 10 to 20% in men and 15-25% in woman. Body fat mass is influenced by interactions among environmental, psychosocial and genetic factors. Promotion of positive energy balance causes obesity in humans as well as in mice (for review see [4,20,33]).The mouse has proven itself as an excellent model for investigations on human diseases as development and genetics are similar in mouse and man. Furthermore, genetic engineering techniques in the mouse became wellestablished and reliable tools in the last two decades. In this mini review we highlight different mouse models which have been instrumental to study body weight regulation and the development of obesity.The melanocortin system and its role in the regulation of energy homeostasisThe lipostatic hypothesis for the control of food intake postulates that adipose tissue produces a hormone in proportion to the amount of fat and acts on the central nervous system to reduce feeding and increase energy expenditure for maintaining energy balance [32].

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Section: Mouse Models With Mutations In the Melanocortin Systemmentioning

confidence: 98%

Mouse models for the central melanocortin system

Bolze

Klingenspor

2009

Genes Nutr

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“…ATRN, ATRNL1, and MEGF8 not only share homology in their ectodomains but they are also the only proteins in the mammalian proteome to share a specific motif (MASRPFAXVXV) of unknown function in their cytoplasmic tails (Walker et al, 2007). We recently demonstrated that transgenic overexpression of Atrnl1 can rescue the pigmentation, reduced myelination, and spongiform neurodegeneration phenotypes of Atrn mutant mice despite the fact that Atrnl1 mutants have no discernable phenotypes of their own (Walker et al, 2007). Given the additive effects of dal and Atrn mg-3J on pigmentation and CNS and testicular vacuolation, we mated dal mutants to our Atrnl1 transgenic founder to determine whether overexpression of Atrnl1 could also rescue the phenotypes of dal mutant mice.…”

Section: Overexpression Of Atrnl1 Does Not Rescue Dal Mutant Phenotypesmentioning

confidence: 99%

“…Male and female A y /A; dal/dal, A y /A; dal/1, and A y /A; 1/1 were weighed and measured (snout to base of tail) at 4-5 months of age. Tg(Atrnl1)B4Tmg mice, which express Atrnl1 under control of the human b-actin promoter, were generated and genotyped as previously described (Walker et al, 2007). The Tg(Atrnl1)B4Tmg founder male was mated to C3;CB-dal/dal females and the F1 progeny backcrossed to C3;CB-dal/dal mice to generate dal/dal mice segregating for the transgene.…”

Section: Mice and Genotypingmentioning

confidence: 99%

“…F2 animals homozygous for Atrn mg-3J were genotyped for dal using a polymorphic microsatellite marker just proximal to the dal locus (D7Mit341 at 25,147,147,230 bp; none of the distal markers we tested were polymorphic between C3H and CBA), and dal homozygotes were genotyped for Atrn mg-3J using primers described previously (Walker et al, 2007). Recombination between dal and D7Mit341 could result in misclassification of dal genotype for up to 6.5% of Atrn mg-3J homozygotes, but this is unlikely to have a strong impact on the data as the incidence of the traits we examined was higher than this and most traits were variable even when genotype was known with certainty.…”

Section: Mice and Genotypingmentioning

confidence: 99%

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Genetic and phenotypic studies of the dark‐like mutant mouse

Cota

Liu

Sumberac

et al. 2008

Genesis

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The dark-like (dal) mutant mouse has a pleiotropic phenotype that includes dark dorsal hairs and reproductive degeneration. Their pigmentation phenotype is similar to Attractin (Atrn) mutants, which also develop vacuoles throughout the brain. In further characterizing the testicular degeneration of dal mutant males, we found that they had reduced serum testosterone and developed vacuoles in their testes. Genetic crosses placed dal upstream of the melanocortin 1 receptor (Mc1r) and downstream of agouti, although dal suppressed the effect of agouti on pigmentation but not body weight. Atrn(mg-3J) and dal showed additive effects on pigmentation, testicular vacuolation, and spongiform neurodegeneration, but transgenic overexpression of Attractin-like-1 (Atrnl1), which compensates for loss of ATRN, did not rescue dal mutant phenotypes. Our results suggest dal and Atrn function in the same pathway and that identification of the dal gene will provide insight into molecular mechanisms of vacuolation in multiple cell types.

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“…It is also possible that additional molecules may mediate some parts of this interaction. For example, ATRNL1 (attractin-like 1), is an ATRN homolog that has been shown to interact with the C terminus of MC4R (52) and, when overexpressed, can compensate for loss of ATRN (53). However, because loss-of-function mutations in Atrnl1 show no pigmentary or body weight phenotypes (53) its direct role, if any, in melanocortin biology remains unclear.…”

Section: Mgmentioning

confidence: 99%

Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein

Overton

Leibel

2011

Journal of Biological Chemistry

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The ubiquitous overexpression of agouti-signaling protein (ASP), a paracrine-signaling molecule that regulates pigmenttype switching in the hair follicle of the mouse, is responsible for the obesity and yellow pelage of the Yellow mouse (A y ). Mahogany (Attractin, Atrn/mg) and mahoganoid (Mahogunin Ring Finger-1, Mgrn1/md) are mutations epistatic to A y . These mutations have been described as suppressors of ASP action, blocking its antagonizing effects on the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unknown mechanisms. Here, we describe the molecular bases for the md-and mg-dependent rescue of the A y phenotype at the MC4R. We show that overexpression of ASP inhibits the rise in cAMP levels in response to ␣-melanocyte-stimulating hormone, an MC4R agonist, by blocking ligand binding and by directing MC4R trafficking to the lysosome. Loss-of-function of either attractin or MGRN1 blocks ASP-dependent MC4R degradation and promotes increased trafficking of internalized MC4R to the cell surface, but it does not restore ␣-melanocytestimulating hormone-dependent cAMP signaling. We propose that MGRN1 and attractin are components of an evolutionarily conserved receptor trafficking pathway and that the md and mg mutations rescue the A y phenotypes by a primarily cAMP-independent mechanism promoting trafficking of MC4R and likely MC1R away from the lysosome toward the cell surface.

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Genetic analysis of attractin homologs

Cited by 17 publications

References 29 publications

Mouse models for the central melanocortin system

Mouse models for the central melanocortin system

Genetic and phenotypic studies of the dark‐like mutant mouse

Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein

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