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  current news   Press   selected story    
     
  30 May 2014  
  The core and conserved role of MAL is homeostatic regulation of actin levels
 
 



Authors
Lara Salvany, Julius Muller, Ernesto Guccione, and Pernille Rørth

Published in Genes & Development on 15 May 2014.

Abstract 
The transcription cofactor MAL is regulated by free actin levels and thus by actin dynamics. MAL, together with its DNA-binding partner, SRF, is required for invasive cell migration and in experimental metastasis. Although MAL/SRF has many targets, we provide genetic evidence in both Drosophila and human cellular models that actin is the key target that must be regulated by MAL/SRF for invasive cell migration. By regulating MAL/SRF activity, actin protein feeds back on production of actin mRNA to ensure sufficient supply of actin. This constitutes a dedicated homeostatic feedback system that provides a foundation for cellular actin dynamics.

Figure Legend: Transposon mutagenesis induces medulloblastoma.
Identification of direct target genes for mal-d in Drosophila. (A) Stage 10 egg chamber from a mal-dD7 homozygous female. The border cell cluster is labeled by GFP and indicated by a green arrow. Anterior is to the left in this and all other images. Border cells normally migrate from the anterior end and to the oocyte (white asterisk in A and C) by stage 10 (as in C), so migration here is severely defective. DAPI (nuclei) is in gray, and phalloidin (F-actin) is in red. (B) Ovary from a mal-dD7 homozygous female stained with DAPI (gray) and phalloidin (red). (C) Stage 10 egg chamber and ovary (shown in D) from tub mal-d3xGFP; mal-dD7 homozygous females. Ubiquitous expression of mal d3xGFP rescues border cell migration (green arrow) and ovary defects (stained as in A and B). (E) Diagram of strategy to identify direct targets of mal-d. ChIP on tub mald3xGFP; mal-dD7 ovaries identified 168 enriched peaks. Expression profiling of ovaries identified 98 genes with a significant decrease in expression in mal-dD7 homozygous females compared with wild type (OR+). The overlap is the six listed genes. (F, top) Binding profile of Mal-d-GFP to the Actin5C genomic region (blue) represented by score (number of reads per peak). Actin5C mRNA and ORF are indicated below (red). Peaks 2 and 3 (and peak 4) are in the promoter region, and peak 1 is 10 kb upstream. (Below) Aligned genomic regions from other Drosophilids(Drosophila simulans and Drosphila pseudoobscura) (same scale; data from FlyBase). The actin genes are highly conserved, the overall locus organization is similar, and the upstream peak 1 is conserved (blue boxes).

For more information on Pernille RØRTH's laboratory, please click here.