Noncanonical function of Capicua as a growth termination signal in Drosophila oogenesis

Capicua (Cic) proteins are conserved HMG-box transcriptional repressors that control receptor tyrosine kinase (RTK) signaling responses and are implicated in human neurological syndromes and cancer. While Cic is known to exist as short (Cic-S) and long (Cic-L) isoforms with identical HMG-box and associated core regions but distinct N termini, most previous studies have focused on Cic-S, leaving the function of Cic-L unexplored. Here we show that Cic-L acts in two capacities during Drosophila oogenesis: 1) as a canonical sensor of RTK signaling in somatic follicle cells, and 2) as a regulator of postmitotic growth in germline nurse cells. In these latter cells, Cic-L behaves as a temporal signal that terminates endoreplicative growth before they dump their contents into the oocyte. We show that Cic-L is necessary and sufficient for nurse cell endoreplication arrest and induces both stabilization of CycE and down-regulation of Myc. Surprisingly, this function depends mainly on the Cic-L–specific N-terminal module, which is capable of acting independently of the Cic HMG-box–containing core. Mirroring these observations, basal metazoans possess truncated Cic-like proteins composed only of Cic-L N-terminal sequences, suggesting that this module plays unique, ancient roles unrelated to the canonical function of Cic.
This work was funded by the Spanish Government (grants BFU2014-52863-P, BFU2017-87244-P, and PID2020-119248GB-I00), the Generalitat de Catalunya (Grant 2017 SGR 475), and the NIH (Grant GM141843). L.R.-M. and C.L. were supported by predoctoral contracts from the Spanish Government.