Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator
Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator
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DOI：
10.1093/hmg/ddi011
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Hammer, GD
中科院分区：
文献类型：
--
作者：
Keegan, CE;Hutz, JE;Hammer, GD
肾上腺皮质发育不良(ACD)是一种自发的常染色体隐性遗传性小鼠突变体，其起源于泌尿生殖道脊的器官存在发育缺陷。在存活的成年突变体中，肾上腺皮质发育不良和功能低下是主要特征。成人由于缺乏成熟的生殖细胞而不育，50%的人由于输尿管增生而发展为肾积水。我们报告了一种新基因的剪接供体突变的鉴定，该基因是一种新发现的端粒调节因子的小鼠同源基因。该基因(ACD)最近被鉴定为TRF1蛋白复合体的一个新的成分，该复合体通过端粒酶控制端粒的伸长。对突变动物的ACD转录本的鉴定显示了两个异常的转录本，与剪接缺陷一致。野生型ACD转基因在ACD突变体中的表达挽救了观察到的表型。大多数突变体在最初的遗传背景下在生命的1-2天内死亡。对这些突变胚胎的分析显示，在尾部规格、肢体图案和轴向骨骼形成方面存在各种但显著的缺陷。在尾芽中，Wnt3a和Dll1的表达减少与尾部退化的表型严重程度相关。在肢体中，Fgf8的表达在顶端外胚脊的背腹轴上扩展，在前后轴上缩短，这与观察到的老年胚胎前指的丧失是一致的。突变胚胎的轴骨显示出颈部、腰部和尾部的异常脊椎融合。这是第一个表明端粒调节分子对于正常的小鼠的泌尿生殖系统脊线分化、轴向骨骼规范和肢体模式是必需的报告。
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.