The Cdc14B phosphatase contributes to ciliogenesis in zebrafish

Abstract

SUMMARYProgression through the cell cycle relies on oscillation of cyclin-dependent kinase (Cdk) activity. One mechanism for downregulating Cdk signaling is to activate opposing phosphatases. The Cdc14 family of phosphatases counteracts Cdk1 phosphorylation in diverse organisms to allow proper exit from mitosis and cytokinesis. However, the role of the vertebrate CDC14 phosphatases, CDC14A and CDC14B, in re-setting the cell for interphase remains unclear. To understand Cdc14 function in vertebrates, we cloned the zebrafish cdc14b gene and used antisense morpholino oligonucleotides and an insertional mutation to inhibit its function during early development. Loss of Cdc14B function led to an array of phenotypes, including hydrocephaly, curved body, kidney cysts and left-right asymmetry defects, reminiscent of zebrafish mutants with defective cilia. Indeed, we report that motile and primary cilia were shorter in cdc14b-deficient embryos. We also demonstrate that Cdc14B function in ciliogenesis requires its phosphatase activity and can be dissociated from its function in cell cycle control. Finally, we propose that Cdc14B plays a role in the regulation of cilia length in a pathway independent of fibroblast growth factor (FGF). This first study of a loss of function of a Cdc14 family member in a vertebrate organism reveals a new role for Cdc14B in ciliogenesis and consequently in a number of developmental processes.

Stages of ciliogenesis and regulation of ciliary length

“…Among them is Cdc14b, an antagonist of Cdk1, which was found to be essential for proper ciliogenesis and ciliary length regulation in zebrafish (Clement et al, 2011). Additionally, the spindle checkpoint regulator BubR1 was found to be required for proper primary cilium formation in fish and humans (Miyamoto et al, 2011).…”

“…Modulation of several cell cycle related kinases can alter ciliary length. In zebrafish Cdc14b, the phosphatase that antagonizes Cdk1, was required for both primary and motile cilia to reach full length (Clement et al, 2011). In Chlamydomonas , a hypomorphic mutation of a CDK related kinase Lf2p results in excessively long flagella, while null mutants have stumpy flagella that are often of unequal flagellar length (Tam et al, 2007).…”

The human phosphatase CDC 14A modulates primary cilium length by regulating centrosomal actin nucleation

“…The cilia length phenotype was specific to hCDC14A and was not observed in cells lacking the paralogue hCDC14B. In contrast to RPE1 cells, cdc14A or cdc14B depletion in zebrafish led to shorter cilia [14,33], Presently, it is unclear why inactivation of CDC14A in zebrafish and human cells impacts cilia length in opposite ways. Variations in cilia phenotypes between organisms upon inactivation of orthologs have been reported before [34].…”

Control of Cdc14 activity coordinates cell cycle and development in Caenorhabditis elegans

“…These similarities suggest conservation with Cdc14A, however, our observations of cdc-14 function are more consistent with the reported role of human Cdc14B in the control of G 1 progression (Rodier et al, 2008). Since Cdc14B has also been associated with DNA-damage checkpoint (Bassermann et al, 2008), meiotic progression (Schindler and Schultz, 2009), centriole replication (Wu et al, 2008) and most recently, ciliogenesis (Clement et al, 2011), it will be interesting to see if similar defects are revealed in cdc-14 mutant worms. Since C. elegans cdc-14 acts as a component of a larger regulatory network, we expect that future studies of Cdc14 in higher organisms will connect specific developmental pathways to cell-cycle regulation and provide further insights into the coordination of development and cell cycle progression.…”