Mouse Models of Human Familial Paraganglioma

Maher, L. James; Smith, Emily H.; Rueter, Emily M.; Becker, Nicole A.; Bida, John P.; Nelson-Holte, Molly; Palomo, José Ignacio Piruat; García-Flores, Paula; López‐Barneo, José; Deursen, Jan van

doi:10.5772/25346

Cited by 13 publications

(14 citation statements)

References 76 publications

(77 reference statements)

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“…We originally set out to develop a mouse model of familial PPGL triggered by loss of SDH. The field has been plagued by the lack of such mouse models of tumorigenesis, and limited cell line models 15,16,18,[29][30][31] though recent progress has been reported in rat. 32 It is possible that the time required for spontaneous LOH in heterozygous SDH-loss mice is too long for development of slow-growing PGL tumors given the short lifespan of the animal.…”

Section: Discussionmentioning

confidence: 99%

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

et al. 2020

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Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH + glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH + cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.

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Section: Discussionmentioning

confidence: 99%

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

et al. 2020

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“…We also utilized a mouse model with an Sdhb heterozygous deletion (Maher III et al, 2011). Unlike in humans (where there is high penetrance of PGL in individuals with SDHB mutations) no PGLs or GISTs or any other tumors have been detected in Sdhb +/− mice (42), except for the recent description by our laboratory of modest pituitary gland hyperplasia and increased growth hormone and prolactin secretion (Xekouki et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Sdhb +/− mice (obtained from Dr. Maher) (Louis J. Maher III, 2011) were maintained on a C57BL/6 genetic background. Mice were sacrificed (CO 2 inhalation) at 12 months of age (n=4; all female) and gastrointestinal tissue (GIT) was dissected.…”

Section: Methodsmentioning

confidence: 99%

Carney triad, SDH-deficient tumors, and Sdhb+/− mice share abnormal mitochondria

Szarek¹,

Ball²,

Impériale³

et al. 2015

Endocrine-Related Cancer

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Carney Triad(CTr) describes the association of paragangliomas(PGL), pulmonary chondromas, and gastrointestinal(GI) stromal tumors(GISTs) with a variety of other lesions including pheochromocytomas and adrenocortical tumors. The gene(s) causing CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues carrying SDH defects but they have not been studied in CTr. For this study, we examined mitochondrial structure in human tumors and GI tissue(GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), and those with isolated GIST(n=1), with CSS caused by SDHC(n=1), SDHD(n=2) mutations were studied by electron microscopy (EM). GIT from mice with a heterozygous deletion in Sdhb (Sdhb+/−, n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GIST of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained increased mitochondria with “hypoxic” phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities and of variable size. Occasionally, mitochondria were small/round, rarely thin, elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. Similar mitochondrial hypoxic phenotype was seen in Sdhb+/− mice. We conclude tissues from SDH-deficient tumors and mouse GIT and from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still elusive CTr defect(s) is(are) likely to affect mitochondrial function just like germline SDH-deficiency.

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“…Two conditional SDHD KO were reported, but none of these models resulted in PPGL development ( 49 ). Two different teams published negative results regarding engineering a SDHB -deficient mouse model ( 50 , 51 ). The failure to develop a pure SDHB KO model suggests a cellular lethality of SDHB complete KO in mice.…”

Section: Mouse Modelsmentioning

confidence: 99%

Pheochromocytoma/paraganglioma preclinical models: which to use and why?

Martinelli

Maggi

Rapizzi

2020

Endocrine Connections

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Pheochromocytomas/paragangliomas (PPGLs) are rare neuroendocrine tumours linked to more than 15 susceptibility genes. PPGLs present with very different genotype/phenotype correlations. Certainly, depending on the mutated gene, and the activated intracellular signalling pathways, as well as their metastatic potential, each tumour is immensely different. One of the major challenges in in vitro research, whatever the study field, is to choose the best cellular model for that study. Unfortunately, most of the time there is not “a best” cell model. Thus, in order to avoid observations that could be related to and/or dependent on a specific cell line, researchers often perform the same experiments using different cell lines simultaneously. The situation is even more complicated when there are only very few cell models obtained in different species for a disease. This is the case for PPGLs. In this review, we will describe the characteristics of the different cell lines and of mouse models, trying to understand if there is one that is more appropriate to use, depending on which aspect of the tumours one is trying to investigate.

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Mouse Models of Human Familial Paraganglioma

Cited by 13 publications

References 76 publications

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency

Carney triad, SDH-deficient tumors, and Sdhb+/− mice share abnormal mitochondria

Pheochromocytoma/paraganglioma preclinical models: which to use and why?

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