Academic journal article Genetics

Drosophila Couch Potato Mutants Exhibit Complex Neurological Abnormalities Including Epilepsy Phenotypes

Academic journal article Genetics

Drosophila Couch Potato Mutants Exhibit Complex Neurological Abnormalities Including Epilepsy Phenotypes

Article excerpt

ABSTRACT

RNA-binding proteins play critical roles in regulation of gene expression, and impairment can have severe phenotypic consequences on nervous system function. We report here the discovery of several complex neurological phenotypes associated with mutations of couch potato (cpo), which encodes a Drosophila RNA-binding protein. We show that mutation of cpo leads to bang-sensitive paralysis, seizure susceptibility, and synaptic transmission defects. A new cpo allele called cpo^sup EG1^ was identified on the basis of a bang-sensitive paralytic mutant phenotype in a sensitized genetic background (sda/+). In heteroallelic combinations with other cpo alleles, cpo^sup EG1^ shows an incompletely penetrant bang-sensitive phenotype with ~30% of flies becoming paralyzed. In response to electroconvulsive shock, heteroallelic combinations with cpo^sup EG1^ exhibit seizure thresholds less than half that of wild-type flies. Finally, cpo flies display several neurocircuit abnormalities in the giant fiber (GF) system. The TTM muscles of cpo mutants exhibit long latency responses coupled with decreased following frequency. DLM muscles in cpo mutants show drastic reductions in following frequency despite exhibiting normal latency relationships. The labile sites appear to be the electrochemical GF-TTMn synapse and the chemical PSI-DLMn synapses. These complex neurological phenotypes of cpo mutants support an important role for cpo in regulating proper nervous system function, including seizure susceptibility.

RNA-BINDING proteins perform myriad crucial roles throughout the life of an RNA molecule in eukaryotes. Subsequent to their genesis in the nucleus during transcription, pre-messenger RNAs (pre-mRNA's) are bound by RNA-binding proteins, which mediate their maturation into mRNA's via processing reactions, such as splicing, editing, capping, and polyadenylation. RNAbinding proteins then assist in transporting mRNA's to the cytoplasm where they are instrumental in regulating the translation, stability, and localization of the transcripts. In addition to translated RNAs, the discovery of regulatory nontranslated RNA genes, termed micro RNA's because of their minuscule size (<100 nucleotides) suggests additional functions for RNA-binding proteins (AMBROS 2001). Thus, RNA-binding proteins serve a most critical role in the control of gene expression, especially in the nervous system where extensive alternative splicing occurs and aberrations frequently result in neurological disease.

Many neurological disorders result when the performance of RNA-binding proteins goes awry, highlighting their importance in the maintenance of fundamental neuronal processes. For example, in the human neurological condition paraneoplastic opsoclonus myoclonus ataxia (POMA), patients lose inhibitory control of motor neurons in spinal cord and brainstem. POMA is associated with the ectopic expression of the NOVA family of RNA-binding proteins, which regulate neuronspecific alternative splicing (JENSEN et al. 2000a,b). In humans with fragile X syndrome, impaired expression of the cytoplasmic RNA-binding protein, FMRP, leads to mental retardation, likely resulting from misregulation of mRNA transport or translation (PEKRONE-BIZZOZERO and BOLOGNANI 2002).

Several neurological disorders that have been characterized in animal models with defective RNA-binding proteins include jerky and quaking in mice and pumilio in Drosophila. The jerky mice exhibit temporal lobe epilepsy analogous to the most common seizure disorder in human adults. The jerky gene encodes an RNAbinding protein postulated to regulate mRNA usage in neurons, which is inactivated in the mutant (Liu et al. 2002). The quaking mice exhibit tonic-clonic seizures and hypomyelination. An RNA-binding protein involved with mRNA nuclear export appears responsible for the "quaking" defects (LAROCQUE et al. 2002). In Drosophila, pumilio mutants show defects in embryonic development and maintenance of neuronal excitability. …

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