{"title":"Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia.","authors":"Noboru Uchida, Tomohiro Ishii, Naoko Amano, Shuji Takada, Kyoko Kobayashi, Tomoaki Murakami, Satoshi Narumi, Tomonobu Hasegawa","doi":"10.1530/JME-24-0015","DOIUrl":null,"url":null,"abstract":"<p><p>Wnt/β-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/β-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating β-catenin expression, eventually developing congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. The adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth but became enlarged with age. Moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone comprised of cells with large nuclei between the ZF and medulla were observed at 6 weeks of age. Immunohistochemistry revealed low levels of 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, in Znrf3Δ2/Δ2 mice. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. Transcriptome analyses of the adrenal glands revealed substantial downregulation of X-zone markers but no significant changes in the expression of genes involved in the Wnt/β-catenin signaling pathway. These results show that a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, and X-zone dysplasia.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of molecular endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1530/JME-24-0015","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Wnt/β-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/β-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating β-catenin expression, eventually developing congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. The adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth but became enlarged with age. Moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone comprised of cells with large nuclei between the ZF and medulla were observed at 6 weeks of age. Immunohistochemistry revealed low levels of 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, in Znrf3Δ2/Δ2 mice. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. Transcriptome analyses of the adrenal glands revealed substantial downregulation of X-zone markers but no significant changes in the expression of genes involved in the Wnt/β-catenin signaling pathway. These results show that a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, and X-zone dysplasia.
期刊介绍:
The Journal of Molecular Endocrinology is an official journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology and the Endocrine Society of Australia.
Journal of Molecular Endocrinology is a leading global journal that publishes original research articles and reviews. The journal focuses on molecular and cellular mechanisms in endocrinology, including: gene regulation, cell biology, signalling, mutations, transgenics, hormone-dependant cancers, nuclear receptors, and omics. Basic and pathophysiological studies at the molecule and cell level are considered, as well as human sample studies where this is the experimental model of choice. Technique studies including CRISPR or gene editing are also encouraged.