Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia

in Journal of Molecular Endocrinology
Authors:
Noboru Uchida Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

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Tomohiro Ishii Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

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Naoko Amano Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
Department of Pediatrics, Saitama City Hospital, Saitama, Japan

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Shuji Takada Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan

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Kyoko Kobayashi Laboratory of Veterinary Toxicology, Tokyo University of Agriculture and Technology, Tokyo, Japan

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Tomoaki Murakami Laboratory of Veterinary Toxicology, Tokyo University of Agriculture and Technology, Tokyo, Japan

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Satoshi Narumi Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

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Tomonobu Hasegawa Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

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Correspondence should be addressed to T Hasegawa: thaseg@keio.jp
DOI:
https://doi.org/10.1530/JME-24-0015
Volume/Issue:
Volume 73: Issue 4
Article Type:
Research Article
Article ID:
e240015
Online Publication Date:
07 Oct 2024
Copyright:
© the author(s) 2024
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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 and eventually leading to the development of congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3 Δ2/Δ2) mice. Whereas the adrenal glands of Znrf3 Δ2/Δ2 mice did not show gross morphological changes at birth, moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone with macrophage infiltration between the ZF and medulla were observed at 6 weeks of age. 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, was hardly detected by immunostaining, and gene expression was significantly downregulated. The number of activated β-catenin-positive cells decreased in the zona glomerulosa, consistent with the results of in situ hybridization for Axin2, a Wnt/β-catenin target gene. Plasma ACTH and serum corticosterone levels in Znrf3 Δ2/Δ2 mice did not differ significantly from those in wild-type mice. These results show a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3 Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, X-zone dysplasia, and macrophage infiltration occurred in the inner cortex.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© the author(s) 2024
Article ID:
e240015
Article Type:
Research Article
Received Date:
20 Feb 2024
Accepted Date:
04 Sep 2024
Print Publication Date:
01 Nov 2024
Online Publication Date:
07 Oct 2024
Keywords:
adrenocortical development; Wnt/β-catenin signaling pathway; zinc and ring finger 3; murine model

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