Abstract
The LC8 family of small ~8 kD proteins are highly conserved and interact with multiple protein partners in eukaryotic cells. LC8-binding modulates target protein activity, often through induced dimerization via LC8:LC8 homodimers. Although many LC8-interactors have roles in signaling cascades, LC8’s role in developing epithelia is poorly understood. Using the Drosophila wing as a developmental model, we find that the LC8 family member Cut up (Ctp) is primarily required to promote epithelial growth, which correlates with effects on the pro-growth factor dMyc and two genes, diap1 and bantam, that are classic targets of the Hippo pathway coactivator Yorkie. Genetic tests confirm that Ctp supports Yorkie-driven tissue overgrowth and indicate that Ctp acts through Yorkie to control bantam (ban) and diap1 transcription. Quite unexpectedly however, Ctp loss has inverse effects on ban and diap1: it elevates ban expression but reduces diap1 expression. In both cases these transcriptional changes map to small segments of these promoters that recruit Yorkie. Although LC8 complexes with Yap1, a Yorkie homolog, in human cells, an orthologous interaction was not detected in Drosophila cells. Collectively these findings reveal that that Drosophila Ctp is a required regulator of Yorkie-target genes in vivo and suggest that Ctp may interact with a Hippo pathway protein(s) to exert inverse transcriptional effects on Yorkie-target genes.
Highlights
The LC8 family of cytoplasmic dynein light-chains, which includes vertebrate LC8 and Drosophila Cut-up (Ctp), are small highly conserved proteins that are ubiquitously expressed and essential for viability[1,2,3,4]
We define a role for the Drosophila protein Cut up (Ctp), a member of the LC8 protein family, in regulating expression of two Hippo target genes, th/diap[1] and bantam, in larval disc cells
Ctp is a member of a highly conserved family (Ctp, Dlc[1], and DYNNL1/DYNNL2) of small proteins that were first identified as components of cytoplasmic dynein motors[1,5,6] but are recognized to act as interaction hubs for many proteins with roles in diverse processes such as autophagy, signal transduction, cell:cell adhesion, and transcription[3,7,8]
Summary
The LC8 family of cytoplasmic dynein light-chains, which includes vertebrate LC8 (aka DYNLL1/DYNLL2) and Drosophila Cut-up (Ctp), are small highly conserved proteins that are ubiquitously expressed and essential for viability[1,2,3,4]. A recent study linked ctp mRNA expression to the zinc-finger transcription factor dASCIZ and showed that knockdown of either Ctp or dASCIZ reduces wing size[22] This diversity of effects produced by Ctp loss in different Drosophila cell types suggest that Ctp plays important yet context specific roles in vivo. Epistasis experiments confirm that Yki is required to activate the bantam promoter in Ctp-depleted cells, and that transgenic expression of Yki can overcome the block to diap[1] transcription In sum these data argue that Ctp supports physiologic Hippo signaling in wing disc epithelial cells, and that Ctp likely interacts with an as yet unidentified Hippo pathway protein(s) to exert inverse transcriptional effects on Yorkie-target genes. These types of inverse effects have not previously been described within the Hippo pathway, and imply that distinct subsets of genes within the Yorkie transcriptome can be simultaneously activated and repressed in developing tissues via a mechanism that involves Ctp
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