Whole-Genome and Poly(A)+Transcriptome Analysis of the Drosophila Mutant agnts3 with Cognitive Dysfunctions

The temperature-sensitive <i>Drosophila</i> mutant <i>agn^ts3</i> exhibits the restoration of learning defects both after heat shock (HS) and under hypomagnetic conditions (HMC). Previously, <i>agn^ts3</i> was shown to have an increased level of LIM kinase 1 (LIMK1). However, its <i>limk1</i> sequence did not significantly differ from that of the wild-type strain <i>Canton-S</i> (<i>CS</i>). Here, we performed whole-genome and poly(A)-enriched transcriptome sequencing of <i>CS</i> and <i>agn^ts3</i> males normally, after HMC, and after HS. Several high-effect <i>agn^ts3</i>-specific mutations were identified, including <i>MED23</i> (regulation of HS-dependent transcription) and <i>Spn42De</i>, the human orthologs of which are associated with intellectual disorders. Pronounced interstrain differences between the transcription profiles were revealed. Mainly, they included the genes of defense and stress response, long non-coding RNAs, and transposons. After HS, the differences between the transcriptomes became less pronounced. In <i>agn^ts3</i>, <i>prosalpha1</i> was the only gene whose expression changed after both HS and HMC. The normal downregulation of <i>prosalpha1</i> and <i>Spn42De</i> in <i>agn^ts3</i> was confirmed by RT-PCR. Analysis of <i>limk1</i> expression did not reveal any interstrain differences or changes after stress. Thus, behavioral differences between CS and <i>agn^ts3</i> both under normal and stressed conditions are not due to differences in <i>limk1</i> transcription. Instead, <i>MED23</i>, <i>Spn42De,</i> and <i>prosalpha1</i> are more likely to contribute to the <i>agn^ts3</i> phenotype.