Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells

Author:

Lewis Elizabeth P.1,Al Khazal Fatimah1,Wilbanks Brandon1ORCID,Gades Naomi M.2,Ortega‐Sáenz Patricia3,López‐Barneo José3,Adameyko Igor45,Maher L. James1ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology Mayo Clinic College of Medicine and Science Rochester Minnesota USA

2. Department of Comparative Medicine Mayo Clinic Scottsdale Arizona USA

3. Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla Sevilla Spain

4. Department of Physiology and Pharmacology Karolinska Institutet Solna Sweden

5. Department of Neuroimmunology, Center for Brain Research Medical University of Vienna Vienna Austria

Abstract

AbstractIn humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.

Funder

Mayo Clinic

Paradifference foundation

Cancerfonden

Vetenskapsrådet

Austrian Science Fund

H2020 European Research Council

Publisher

Wiley

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