Ubiquitination is a particularly versatile post-translational modification that influences most, if not all, aspects of cellular biology 
. Conjugation of ubiquitin to a target protein occurs through an conserved enzymatic cascade that involves a ubiquitin activating enzyme (also called E1), a ubiquitin conjugating enzyme (E2) as well as a ubiquitin ligase (E3). E3 ligases confer substrate specificity to the ubiquitination reaction. In light of this crucial function, it is not surprising that many E3 ligases exist 
. Among these, the Cullin RING E3 ligases (CRLs) are the largest family 
CRLs are modular protein complexes that are formed on a characteristic scaffold subunit of the Cullin protein family 
. The conserved C-terminal domain of the Cullin recruits a RING protein that enables the association of the CRL with an E2 conjugating enzyme. The N-terminal domain of the Cullin associates with a substrate receptor protein, which in turn recruits the target of the ubiquitination reaction. In some cases, adaptor proteins form a bridge between the Cullin and its substrate receptors. By bringing them in close proximity, the Cullin enables the transfer of ubiquitin from the E2 enzyme to the target protein. Notably, each Cullin can associate with several different substrate receptors, which moreover may recognize multiple targets. Therefore, the number of proteins regulated by a given Cullin can be quite large. Consequently, it is not surprising that Cullins have been implicated in many aspects of cellular biology, ranging from cell cycle progression, modulation of intra- and intercellular pathways, chromatin remodelling and many more.
Cullin-5 (Cul-5) has been most extensively studied in the context of viral infection 
, and has recently been implicated in the regulation of the non-receptor tyrosine kinase Src 
. However, comparatively little is known about Cul-5 function in developmental and morphogenetic processes. In Drosophila
, certain genetic manipulations of cul-5
have been reported to affect epidermal patterning, synapse formation and sensory organ development 
. In mice, Cul-5 is involved in neuron positioning during development of the brain cortex 
. These findings indicate that Cul-5 is involved in various developmental and morphogenetic processes.
oogenesis provides an excellent model system to study different aspects of cellular biology, intercellular communication and tissue morphogenesis 
. During oogenesis, mature eggs develop from multicellular progenitor structures called egg chambers. Egg chambers are produced in higher order structures called ovarioles in which progressively more mature egg chambers are lined up in a linear fashion. Each egg chamber contains a cyst (or cluster) of 16 interconnected germ cells (cystocytes) that arises from a common stem cell-derived progenitor (the cystoblast) through four rounds of synchronous mitotic divisions. Germ line stem cell (GSC) and subsequent cystocyte divisions take place in the most apical portion of the ovariole, in regions 1 and 2A of the germarium. Cystocyte divisions are incomplete, and the daughter cells remain connected by cytoplasmic bridges, called ring canals, that are stabilized as F-actin-rich structures. These allow the passage of material between cystocytes. Only one of the cyst cells enters meiosis and adopts an oocyte fate, while the other 15 endoreplicate and differentiate into nurse cells, which provide macromolecules and organelles to the developing oocyte.
In region 2B of the germarium, each germ line cyst becomes encapsulated by a monolayered follicular epithelium of somatic origin 
. The follicular epithelium plays crucial roles in establishing and maintaining polarity of the egg chambers, and secretes the eggshell during late oogenesis before its own degeneration 
. Proper development of the follicular epithelium and consequently egg chamber morphogenesis requires communication between germ line and somatic cells as well as among follicle cells themselves, and involves among others the Notch/Delta and EGF receptor signalling pathways. In region 3 of the germarium, individual follicles bud off the germarium and enter the vitellarium.
Here, we demonstrate that reduced cul-5
function leads to the formation of aberrantly formed follicles that are most frequently characterized by an excess of germ line cells. Their formation results both from germ cell overproliferation in the germarium, and improper clustering of germ cell cysts into inappropriately sized follicles. These phenotypes are drastically enhanced by sensitizing the cul-5
mutant background by reducing genetic dosage of the Cul-5 CRL receptor Gustavus (Gus) 
(JM.K. and P.L., submitted), indicating that Cul-5 acts at least in part through Gus to ensure normal ovarian morphogenesis.
Intriguingly, cul-5 mutant ovarioles also display a partially penetrant germ cell depletion phenotype. Again, this phenotype is drastically enhanced by simultaneous reduction of the Cul-5 substrate receptor Gus. We therefore establish a novel functional link between a Cul-5 CRL and GSC maintenance or germ cell survival.