The transcriptional co-repressor CtBP is a negative regulator of growth that antagonizes the Yorkie and JNK/AP-1 pathways

Abstract

Multicellular organisms require strict growth control mechanisms to ensure that an organ reaches, but does not grossly exceed, its appropriate size and shape. In an unbiased mosaic screen for genes involved in growth regulation, we identified a loss-of-function allele of the gene CtBP that conferred a growth advantage to homozygous mutant tissue. CtBP encodes a transcriptional co-repressor found in diverse organisms, yet its role in regulating tissue growth is not known. We found that CtBP functions as a negative regulator of growth by restricting the expression of the growth-promoting microRNA bantam (ban). ban is a known target of the Hippo pathway effector Yorkie (Yki). We show that loss of CtBP function leads to the activation of a minimal enhancer of ban via both Yki-dependent and AP-1 transcription factor-dependent mechanisms. AP-1 is downstream of the Jun N-terminal Kinase (JNK) pathway and thus JNK could regulate growth during development via ban. Furthermore, we show that distinct isoforms of the AP-1 component Fos differ in their ability to activate this enhancer. Since the orthologous pathways in mammalian cells (YAP/TEAD and AP-1) converge on enhancers implicated in tumor progression, a role for mammalian CtBP proteins at those enhancers merits attention.

The JNK and Hippo pathways control epithelial integrity and prevent tumour initiation by regulating an overlapping transcriptome

“…In addition, DIAP1-lacZ , brC12 -lacZ and ban3-GFP were all elevated in CtBP 87De10 , scrib 1 clones (Figures 5H-J’, S5C, S5F and S5H-J). DIAP1-lacZ and ban3-GFP were unchanged in single mutant clones, whilst brC12 -lacZ was unchanged in scrib 1 clones and mildly elevated in CtBP 87De10 clones (Figures 5E-5I’, S5A, B, D, E and S5H-J), consistent with a study that assessed ban CtBP wing imaginal disc clones 57 .…”

“…To investigate this further, we used RNA-seq to profile the transcriptome of late third instar larval eye imaginal discs harbouring predominantly CtBP 87De10 tissue or CtBP 87De10 , scrib 1 double mutant tissue. CtBP 87De10 eyes had minor transcriptional changes compared to wild-type eyes, consistent with the fact that CtBP eye tissue has only a very mild growth advantage and normal tissue morphology 57 (Figures 5B and 5L). By contrast, the transcriptome of CtBP 87De10 , scrib 1 eyes differed substantially from either control eyes or CtBP 87De10 eyes (Figures 5L).…”

“…Loss of different Polycomb group genes induces dramatic overgrowth of D. melanogaster imaginal discs 55,56 , and Polycomb group members influence neoplastic tissue growth and transcription in imaginal discs from homoygous scrib larvae 44 . CtBP loss causes very mild overgrowth of imaginal discs, while CtBP and certain isoforms of Fos repress transcription of ban , which is a target of both Yki/Sd and AP-1 57 . To test potential roles for Polycomb group genes and CtBP in repression of transcription in scrib clones, we first used genetic mosaic experiments.…”

Pits and CtBP control tissue growth in Drosophila melanogaster with the Hippo pathway transcription repressor, Tgi

“…As reported previously, generation of tissue homozygous mutant for the hypomorphic sav 2 allele caused mild eye and head overgrowth (Figure 2A) (TAPON et al 2002). Eye and head overgrowth was also observed when tissue was homozygous for the strong loss of function CtBP allele CtBP 87De-10 , consistent with prior studies (HOANG et al 2010;SUMABAT 2019), although the overgrowth phenotype was weaker than for sav 2 (Figure 2A). Strikingly, eye and head tissue that was double mutant for both sav 2 and CtBP 87De-10 displayed dramatic overgrowth, somewhat resembling null alleles of sav such as sav 3 and sav shrp1 (Figure 2A) (KANGO-SINGH et al 2002;TAPON et al 2002).…”