Mozer B A
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dev Biol. 2001 May 15;233(2):380-93. doi: 10.1006/dbio.2001.0229.
Dominant Drop (Dr) mutations are nearly eyeless and have additional recessive phenotypes including lethality and patterning defects in eye and sensory bristles due to cis-regulatory lesions in the cell cycle regulator string (stg). Genetic analysis demonstrates that the dominant small eye phenotype is the result of separate gain-of-function mutations in the closely linked muscle segment homeobox (msh) gene, encoding a homeodomain transcription factor required for patterning of muscle and nervous system. Reversion of the Dr(Mio) allele was coincident with the generation of lethal loss-of-function mutations in msh in cis, suggesting that the dominant eye phenotype is the result of ectopic expression. Molecular genetic analysis revealed that two dominant Dr alleles contain lesions upstream of the msh transcription start site. In the Dr(Mio) mutant, a 3S18 retrotransposon insertion is the target of second-site mutations (P-element insertions or deletions) which suppress the dominant eye phenotype following reversion. The pattern of 3S18 expression and the absence of msh in eye imaginal discs suggest that transcriptional activation of the msh promoter accounts for ectopic expression. Dr dominant mutations arrest eye development by blocking the progression of the morphogenetic furrow leading to photoreceptor cell loss via apoptosis. Gal4-mediated ubiquitous expression of msh in third-instar larvae was sufficient to arrest the morphogenetic furrow in the eye imaginal disc and resulted in lethality prior to eclosion. Dominant mutations in the human msx2 gene, one of the vertebrate homologs of msh, are associated with craniosynostosis, a disease affecting cranial development. The Dr mutations are the first example of gain-of-function mutations in the msh/msx gene family identified in a genetically tractible model organism and may serve as a useful tool to identify additional genes that regulate this class of homeodomain proteins.
显性缺失（Dr）突变几乎无眼，并且具有其他隐性表型，包括致死性以及由于细胞周期调节因子串珠（stg）中的顺式调节损伤导致的眼睛和感觉刚毛的模式缺陷。遗传分析表明，显性小眼表型是紧密连锁的肌肉节段同源盒（msh）基因中单独的功能获得性突变的结果，该基因编码肌肉和神经系统模式形成所需的同源结构域转录因子。Dr（Mio）等位基因的回复与顺式作用的msh中致死性功能丧失突变的产生同时发生，表明显性眼表型是异位表达的结果。分子遗传学分析表明，两个显性Dr等位基因在msh转录起始位点上游存在损伤。在Dr（Mio）突变体中，一个3S18反转录转座子插入是第二位点突变（P因子插入或缺失）的靶点，这些突变在回复后抑制显性眼表型。3S18的表达模式以及眼成虫盘中msh的缺失表明，msh启动子的转录激活导致了异位表达。Dr显性突变通过阻断形态发生沟的进展来阻止眼睛发育，导致光感受器细胞通过凋亡而丧失。Gal4介导的msh在三龄幼虫中的普遍表达足以阻止眼成虫盘中的形态发生沟，并导致羽化前死亡。人类msx2基因（msh的脊椎动物同源物之一）中的显性突变与颅缝早闭有关，颅缝早闭是一种影响颅骨发育的疾病。Dr突变是在遗传易处理的模式生物中鉴定出的msh/msx基因家族功能获得性突变的首个例子，可能作为一种有用的工具来鉴定调控这类同源结构域蛋白的其他基因。
