In Development this week (Vol. 143, Issue 4)

Here are the highlights from the current issue of Development:

Fishing out a new role for endocannabinoids

Endocannabinoids (ECs) are signalling molecules that regulate appetite, mood and pain, and they are studied mostly for their effects on the nervous system. Now, on p. 609, Wolfram Goessling and colleagues uncover a role for EC signalling during liver development and function in zebrafish. Using a chemical screen to identify novel regulators of liver development, the researchers reveal that EC agonists cause an increase in liver size. In line with this, they show that the EC receptors Cnr1 and Cnr2 are expressed in the liver and hepatic region of developing embryos. The TALEN-mediated knockout of these receptors disrupts the differentiation and proliferation, but not the specification, of hepatocytes, giving rise to livers that exhibit architectural and metabolic defects. These defects have a negative long-term impact, causing susceptibility to metabolic insult and disruptions to global lipid metabolism in adult fish. Finally, the authors reveal that the effects of EC signalling are mediated by methionine and by sterol regulatory element-binding transcription factors (Srebfs); methionine supplementation or the overexpression of Srebfs can rescue the liver defects of Cnr mutants. Together, these findings define exciting and novel links between EC signalling, methionine metabolism and liver development.

Kidney development: of mice and men

The Six family transcription factors Six1 and Six2 play non-overlapping roles during kidney development in mice: Six1 controls the initial formation of nephron progenitors, which give rise to nephrons (the functional units of the kidney), whereas Six2 controls progenitor self-renewal. How these factors function during kidney development in humans, however, is less clear. Now, Lori O’Brien, Anton Valouev, Andrew McMahon and co-workers reveal that mouse and human nephron progenitors are differentially regulated by Six family factors (p. 595). Using ChIP-seq analyses, they show that, although mouse Six2 and human SIX2 share many common targets, the SIX1 gene is a unique SIX2 target in humans. In line with this, they demonstrate that Six1 expression is transient and independent of Six2 in the mouse embryonic kidney, whereas SIX1 expression persists in human fetal nephron progenitors and is regulated by SIX2. The researchers also show that SIX1 and SIX2 exhibit overlapping activities in human fetal nephron progenitors, binding to similar sets of targets and showing evidence of cross-regulatory activity. These findings highlight a divergence in Six family function that may underlie species-specific differences in kidney development, such as the extended period of nephrogenesis seen in humans.

Tense times for tumour suppressors and proto-oncogenes

Tumour suppressors and proto-oncogenes play fundamental roles in controlling tissue size, shape and organization. It is generally thought that their deleterious effects on tissue development and homeostasis are associated with defects in cell division, but now (p. 623) Yohanns Bellaïche and colleagues reveal mechanical roles for these genes in Drosophila epithelia. They use time-lapse imaging to follow cell behaviour and dynamics in clones of cells that are mutant for the tumour suppressor Fat (Ft). This analysis reveals that Ft mutant clones round up and reduce their cell-cell contacts with surrounding wild-type tissue in the absence of concomitant cell division and over-proliferation. The authors further show that the loss of Ft activity leads to increased levels of the myosin Dachs within clones and the accumulation of Dachs at clone boundaries. Using laser ablation approaches to probe junctional tension, the authors reveal that this polarized distribution of Dachs at clone boundaries increases junctional tension, whereas Dachs accumulation within the clone body decreases tension; these two activities cooperate to promote clone rounding. These findings, together with the analyses of other proto-oncogenes such as Yorkie, Myc and Ras, point to a novel and key function of tumour suppressors and proto-oncogenes.

A new spin on LGN

During cell division, orientation of the mitotic spindle can influence cell fate by controlling the segregation of cell fate determinants. Here, by inactivating the spindle orientation complex protein LGN, Michel Cayouette and co-workers investigate how spindle orientation influences cell fate in two contexts: the mouse retina and the mouse neocortex (p. 575). Their analysis of Lgn-knockout mice reveals that LGN inactivation causes a decrease in the number of vertical divisions (i.e. those occurring with the spindle perpendicular to the neuroepithelium) carried out by retinal progenitor cells (RPCs). By contrast, when looking at the neocortex, they report that LGN increases the incidence of vertical divisions in cortical progenitors. The researchers further show that LGN and hence vertical spindle division in the retina is required for the terminal asymmetric division of RPCs, whereas LGN in the neocortex acts to maintain planar divisions and the self-renewal of cortical progenitors. In summary, these findings demonstrate that LGN inactivation disrupts spindle orientation in both contexts but leads to very different outcomes with regards to cell fate.

PLUS…

The Notch meeting: an odyssey from structure to function

The Notch IX meeting, which was held in Athens, Greece in October 2015, brought together scientists working on different model systems and studying Notch signaling in various contexts. Here, we provide a summary of the key points that were presented at the meeting. Although we focus on the molecular mechanisms that determine Notch signaling and its role in development, we also cover talks describing roles for Notch in adulthood. See the Meeting Review on p. 547

Stomach development, stem cells and disease

The stomach, an organ derived from foregut endoderm, secretes acid and enzymes and plays a key role in digestion. In their Review, Kim and Shivdasani highlight the molecular mechanisms of stomach development and discuss recent findings regarding stomach stem cells and organoid cultures, and their roles in investigating disease mechanisms. See the Review on p.554

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