Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator
Abstract
Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. We report the identification of a splice donor mutation in a novel gene, which is the mouse ortholog of a newly discovered telomeric regulator. This gene (Acd) has recently been characterized as a novel component of the TRF1 protein complex that controls telomere elongation by telomerase. Characterization of Acd transcripts in mutant animals reveals two abnormal transcripts, consistent with a splicing defect. Expression of a wild-type Acd transgene in acd mutants rescues the observed phenotype. Most mutants die within 1-2 days of life on the original genetic background. Analysis of these mutant embryos reveals variable, yet striking defects in caudal specification, limb patterning and axial skeleton formation. In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 is expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos shows abnormal vertebral fusions in cervical, lumbar and caudal regions. This is the first report to show that a telomeric regulator is required for proper urogenital ridge differentiation, axial skeleton specification and limb patterning in mice.
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High-resolution copy number analysis and spectral karyotyping showed non-reciprocal translocations are a major driver of regional amplification or deletion of cancer-relevant genes.
“High-resolution copy number analysis, coupled with spectral karyotyping, have since demonstrated that these non-reciprocal translocations are a major driver of regional amplification or deletion of cancer-relevant genes (106,107).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [107]
These syntenic changes included alterations in known cancer genes NOTCH1, MYB, FBXW7 and PTEN.
“These syntenic changes included alterations in known cancer genes such as NOTCH1, MYB, FBXW7 and PTEN.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [107]
The majority of recurrent CNAs in these murine lymphomas were syntenic to amplified or deleted regions in diverse human cancers.
“Remarkably, the majority of recurrent CNAs in these murine lymphomas were syntenic to amplified/deleted regions in human cancers of diverse types.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [107]
Thymic lymphomas driven by severe telomere dysfunction in G5 TERC-/- ATM-/- p53+/- mice showed abundant focal gene amplifications and deletions by aCGH.
“Thymic lymphomas driven by severe telomere dysfunction in G5 TERCÀ/À ATMÀ/ p53þ/À mice were analyzed by aCGH and showed abundant focal gene amplifications and deletions.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [107]
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- Authors
- Keegan, C. E., Hutz, J. E., Else, T., Adamska, M., Shah, S. P., Kent, A. E., Howes, J. M., Beamer, W. G., & Hammer, G. D.
- Affiliations
- University of Michigan (US)
- Jackson Laboratory (US)
- Corresponding author
- Keegan, Catherine E.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-11-10
- Volume
- 14
- Issue
- 1
- Pages
- 113-123
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2114719839
- Cited by
- 68
- References
- 51
- Citations by year
- 2024: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 2
- FWCI
- 0.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Cancer Institute (CA46592, P30CA046592)
- National Institute of General Medical Sciences (R01GM024872, R01-GM24872)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK20572, R01 DK 62027, R01DK062027)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD 28820, K08HD042487, K12HD028820, K08-HD42487)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Renal and related cancers
- Keywords
- telomere elongation, splicing mutation, limb patterning, vertebral fusion, Wnt3a, DLL1, FGF8, apical ectodermal ridge, germ cell deficiency, hydronephrosis, transgenic rescue, mouse mutants
- MeSH terms
- Animals, Gonadal Dysgenesis, Mice, Mutant Strains, Mutation, RNA Splicing, Telomere, Gene Expression Regulation, Developmental, Body Patterning, Telomeric Repeat Binding Protein 1, Multiprotein Complexes, Mice
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