Reviews & Analysis

Hippo signalling has been associated with many important tissue functions including the regulation of organ size. In the intestinal epithelium differing functions have been proposed for the effectors of Hippo signalling, YAP and TAZ1. These are now shown to have a dual role in the intestinal epithelium, regulating both stem cell proliferation and differentiation along a specific secretory lineage.

The microcephaly protein, Cep215, contributes to the engagement of duplicated centrioles in interphase. Now two distinct pools of Cep215 at centrosomes are identified, one bound to Cep68 and the other to pericentrin. Plk1-mediated degradation of Cep68 and separase-mediated cleavage of pericentrin release both pools of Cep215, thereby promoting centriole disengagement.

The class III phosphoinositide 3-kinase VPS34 regulates autophagosome formation. Three groups have developed VPS34 inhibitors and shown their utility in investigating and defining autophagic processes.

Autophagy is an intracellular degradation system that is mediated by orchestrated functions of membranes and proteins. A genetic screen in Caenorhabditis elegans revealed that O-linked N-acetylglucosamine modification of the SNARE protein SNAP-29 negatively regulates SNARE-dependent fusion between autophagosomes and lysosomes. This regulatory mechanism is conserved in mammals.

The endoderm layer destined to be primitive gut is a mosaic of earlier visceral endoderm and definitive endoderm that arises later, during gastrulation. Live imaging now reveals that in mouse embryos, definitive endoderm cells egress from underlying mesoderm and intercalate into the overlying cell layer. This process requires SOX17-mediated control of basement membrane organization.

Protein quality control systems protect cells from proteotoxicity caused by the accumulation of aberrantly folded polypeptides. The Rsp5 ubiquitin ligase (mammalian homologue Nedd4) is now identified as a major constituent of a clearance pathway that degrades misfolded cytosolic proteins after exposure to heat.

Despite the importance of cyclins and cyclin-dependent kinases (Cdks) in the control of cell division, the physiological role of many of these regulators remains unknown. Cyclin C and its associated kinases Cdk3, Cdk8 and Cdk19 are now shown to function as tumour suppressors in haematopoietic malignancies by inhibiting the Notch1 pathway.

Stat3 has been shown to regulate lysosome membrane permeabilization and cell death in vivo during post-lactation mammary gland involution. It is now revealed that Stat3 induces lysosome membrane permeabilization by causing phagocytosis of milk fat globules, which destabilize the lysosome membrane leading to leakage of cathepsin proteases.

Expansion of a vascular network requires breaking through the basement membrane, a highly crosslinked barrier that tightly adheres to mature vessels. Angiogenic endothelial cells are now shown to form podosome rosettes that are able to focally degrade the extracellular matrix, prior to vascular sprouting in tumour angiogenesis.

The induction of cell reprogramming by transcription factors into alternative cell fates opens new avenues for regenerative medicine. Thymic epithelial cells that were obtained from fibroblasts by Foxn1 overexpression support the formation of an ectopic thymus following transplantation.

ABCC4 is a member of the ATP-binding cassette transporter family known to transport prostaglandin E2 and other molecules across cellular membranes. A mutation in ABCC4 is now shown to cause defects in ciliogenesis, revealing a role for prostaglandin signalling in regulating cilia dynamics.

Anti-tubulin drugs are life-saving chemotherapeutics that kill cancer cells by stabilizing or disrupting microtubules. Despite their clinical utility, the molecular mechanisms by which anti-tubulins cause apoptotic cell death remain poorly understood. It is now shown that microtubule disruption can inhibit anti-apoptotic Bcl-2 family proteins through an evolutionarily conserved signalling axis involving DEPDC1 (LET-99 in Caenorhabditis elegans) and JNK.

Lgr5, a marker of stem cells in many organs, is found expressed in cells scattered through the ovarian epithelium that expand to repair and regenerate the damaged ovarian surface after each ovulation. Lgr5-positive stem cells in the ovary and the fimbria of the oviduct may be critical cells of origin for ovarian cancer.

Chromosome instability is a major hallmark of cancer, but its molecular causes are still poorly understood. A study now describes how genetic alterations frequently found in colorectal cancer increase microtubule assembly rates during mitosis and promote chromosome instability.

Mitosis depends upon the action of the mitotic spindle, a subcellular machine that uses microtubules (MTs) and motors to assemble itself and to coordinate chromosome segregation. Recent work illuminates how the motor-driven poleward sliding of MTs — nucleated at centrosomes, chromosomes and on pre-existing MTs — contributes to spindle assembly and length control.

Cell–cell interactions, a key feature of the stem cell niche, regulate many aspects of stem cell behaviour. N-cadherin-mediated anchorage of neural stem cells within the adult neural niche maintains stem cell quiescence, and its release by the metalloproteinase MT5-MMP promotes neural stem cell activation.

Collective cell migration is characterized by the maintenance of intercellular contacts during cell movement. The maintenance of N-cadherin-based junctions during collective migration is now shown to be facilitated by their treadmilling from the cell front to the rear, followed by N-cadherin endocytosis and recycling to the leading edge.

The kinesin-4 motor protein Kif7 regulates Hedgehog signalling at cilia in mammals by controlling the activity of Gli transcription factors. Kif7 is now found to inhibit microtubule growth to restrict and coordinate the length of axonemal microtubules at the ciliary tip. Such Kif7-mediated organization of the ciliary tip compartment regulates Gli activity and is proposed to be required for correct Hedgehog signalling.

Clathrin-independent endocytosis removes membrane receptors and other proteins from the cell surface, yet the mechanisms controlling this process remain unclear. Galectin-3 is now shown to regulate the biogenesis of a subpopulation of clathrin-independent carriers (CLICs). Galectin-3 binds to glycosylated cargo proteins and interacts with membrane glycosphingolipids to induce membrane deformation and CLIC formation.

Cadherin-containing cell–cell junctions respond to intercellular tension by increasing their size, strength and complexity. The mechanical regulation of cadherin adhesions is now shown to involve myosin-dependent tension in the cortical actomyosin cytoskeleton. This reduces actin turnover to decrease the mobility of cadherin molecules and increase their concentration at junctions.