Keegan Catherine E, Hutz Janna E, Else Tobias, Adamska Maja, Shah Sonalee P, Kent Amy E, Howes John M, Beamer Wesley G, Hammer Gary D
Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor, MI 48109-0789, USA.
Hum Mol Genet. 2005 Jan 1;14(1):113-23. doi: 10.1093/hmg/ddi011. Epub 2004 Nov 10.
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.
肾上腺皮质发育异常（acd）是一种自发的常染色体隐性小鼠突变体，其源自泌尿生殖嵴的器官存在发育缺陷。在存活的成年突变体中，肾上腺皮质发育异常和功能减退是主要特征。成年突变体由于缺乏成熟生殖细胞而不育，并且50%会因输尿管增生而出现肾积水。我们报告了在一个新基因中鉴定出一个剪接供体突变，该基因是新发现的端粒调节因子的小鼠直系同源物。这个基因（Acd）最近被表征为TRF1蛋白复合物的一个新组分，该复合物通过端粒酶控制端粒延长。对突变动物中Acd转录本的表征揭示了两种异常转录本，这与剪接缺陷一致。在acd突变体中表达野生型Acd转基因可挽救所观察到的表型。在原始遗传背景下，大多数突变体在出生后1 - 2天内死亡。对这些突变胚胎的分析揭示了在尾端特化、肢体模式形成和轴向骨骼形成方面存在可变但显著的缺陷。在尾芽中，Wnt3a和Dll1表达降低与尾端退化的表型严重程度相关。在肢体中，Fgf8的表达在顶端外胚层嵴的背腹轴上扩展，在前后轴上缩短，这与在较老胚胎中观察到的前指缺失一致。突变胚胎的轴向骨骼在颈椎、腰椎和尾椎区域显示出异常的椎体融合。这是首次报道表明端粒调节因子对于小鼠泌尿生殖嵴的正常分化、轴向骨骼特化和肢体模式形成是必需的。
