Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture

Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or Dlg1 induces atf3 expression via aPKC but independent of Jun-N-terminal kinase (JNK) signaling. Strikingly, removal of Atf3 from Dlg1 deficient cells restores polarized cytoarchitecture, levels and distribution of endosomal trafficking machinery, and differentiation. Conversely, excess Atf3 alters microtubule network, vesicular trafficking and the partition of polarity proteins along the apicobasal axis. Genomic and genetic approaches implicate Atf3 as a regulator of cytoskeleton organization and function, and identify Lamin C as one of its bona fide target genes. By affecting structural features and cell morphology, Atf3 functions in a manner distinct from other transcription factors operating downstream of disrupted cell polarity.Author summaryEpithelial cells form sheets and line both the outside and inside of our body. Their proper development and function require the asymmetric distribution of cellular components from the top to the bottom, known as apicobasal polarization. As loss of polarity hallmarks a majority of cancers in humans understanding how epithelia respond to a collapse of the apicobasal axis is of great interest. Here, we show that in the fruit fly Drosophila melanogaster, the breakdown of epithelial polarity engages Activating transcription factor 3 (Atf3), a protein that directly binds the DNA and regulates gene expression. We demonstrate that many of the pathological consequences of disturbed polarity require Atf3, as its loss in this context results in normalization of cellular architecture, vesicle trafficking and differentiation. Using unbiased genome-wide approaches we identify the genetic program controlled by Atf3 and experimentally verify select candidates. Given the evolutionary conservation of Atf3 between flies and man, we believe that our findings in the Drosophila model will contribute to a better understanding of diseases stemming from compromised epithelial polarity.