Central Regulation of Locomotor Behavior of Drosophila melanogaster Depends on a CASK Isoform Containing CaMK-Like and L27 Domains
Central Regulation of Locomotor Behavior of Drosophila melanogaster Depends on a CASK Isoform Containing CaMK-Like and L27 Domains
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DOI：
10.1534/genetics.110.123406
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发表时间：
2011-01-01
期刊：
影响因子：
3.3
通讯作者：
Griffith, Leslie C.
中科院分区：
文献类型：
--
作者：
Slawson, Justin B.;Kuklin, Elena A.;Griffith, Leslie C.
运动行为障碍的遗传原因可能是由于肌肉、外周神经元或中枢神经系统病变。黑腹果蝇（Drosophila melanogaster）的人类CASK同源物（也称为caki或camguk）是一种分子支架，被认为在运动和可塑性中发挥作用。这些结论是基于使用重叠缺陷的研究，这些重叠缺陷在很大程度上消除了整个CASK基因座，但也包含额外的染色体畸变。更重要的是，对果蝇基因组测序的分析表明，存在来自CASK基因座的多种蛋白变体，这进一步使使用缺陷菌株的实验解释复杂化。在这项研究中，我们在CASK基因中产生了小的缺失，消除了含有CaMK样和L27结构域（CASK-β）的基因产物，但不影响编码较小形式（CASK-α）的转录本，这些转录本在结构上与脊椎动物MPP 1同源。这些突变体具有正常的嗅觉习惯，但表现出一系列惊人的运动问题，包括启动和运动维持缺陷。以前的研究表明，在多基因缺陷株的神经肌肉接头突触前释放缺陷可能是其运动表型的基础。然而，CASK-β突变体的运动表型不能通过在运动神经元中表达CASK-β转基因来拯救。在不包括椭圆体（一种众所周知的前运动神经元）的中枢神经元子集中的表达提供了完全的拯救。全长CASK-β虽然在神经系统中广泛表达，但似乎在控制运动输出的中央回路中具有独特的作用。
Genetic causes for disturbances of locomotor behavior can be due to muscle, peripheral neuron, or central nervous system pathologies. The Drosophila melanogaster homolog of human CASK (also known as caki or camguk) is a molecular scaffold that has been postulated to have roles in both locomotion and plasticity. These conclusions are based on studies using overlapping deficiencies that largely eliminate the entire CASK locus, but contain additional chromosomal aberrations as well. More importantly, analysis of the sequenced Drosophila genome suggests the existence of multiple protein variants from the CASK locus, further complicating the interpretation of experiments using deficiency strains. In this study, we generated small deletions within the CASK gene that eliminate gene products containing the CaMK-like and L27 domains (CASK-beta), but do not affect transcripts encoding the smaller forms (CASK-alpha), which are structurally homologous to vertebrate MPP1. These mutants have normal olfactory habituation, but exhibit a striking array of locomotor problems that includes both initiation and motor maintenance defects. Previous studies had suggested that presynaptic release defects at the neuromuscular junction in the multigene deficiency strain were the likely basis of its locomotor phenotype. The locomotor phenotype of the CASK-beta mutant, however, cannot be rescued by expression of a CASK-beta transgene in motor neurons. Expression in a subset of central neurons that does not include the ellipsoid body, a well-known pre-motor neuropil, provides complete rescue. Full-length CASK-beta, while widely expressed in the nervous system, appears to have a unique role within central circuits that control motor output.