In Development this week (Vol. 143, Issue 17)

Here are the highlights from the current issue of Development:

Coordinating neuronal specification and differentiation

Neurogenesis – the process of making new neurons – is indispensable for normal development and for adult homeostasis and repair. Many of the signalling and transcriptional events that regulate the specification and differentiation of neural progenitor cells (NPCs) into neurons have been uncovered; however, how these events are coordinated at a post-translational level is not well defined. Now, on p.3085, Miho Matsuda, Ajay Chitnis and colleagues identify the protein Epb41l5 – an adaptor protein that links cytoplasmic proteins to specific membrane compartments – as a new regulator of neuronal differentiation in the developing zebrafish hindbrain. The authors first identify Epb41l5 in a yeast two-hybrid screen against Mib1, a key component of the Notch signalling pathway. Using Epb41l5-deficient embryos, the authors show that loss of Epb41l5 impairs neuronal differentiation, but that this can be partially rescued by knockdown of N-cadherin expression, suggesting a possible role for Epb41l5 in the disassembly of apical adherens junctions. In support of this, the authors further demonstrate that Mib binding to Epb41l5 facilitates its degradation and thus promotes apical adhesions, which may impair proper delamination and differentiation. The authors conclude by proposing a model whereby changes in Notch ligand levels that occur during neuronal differentiation protect Epb41l5 from Mib1-mediated degradation, thereby facilitating neuroepithelial detachment and subsequent differentiation.

Sall4 is dispensable for mouse pluripotency

In order to specify the correct lineage at the correct time, the developing embryo must maintain tight control over the gene regulatory networks that enact these changes. Sall4 has long been associated with the regulation of embryonic stem cell (ESC) self-renewal and differentiation; however, teasing out its precise role has been difficult. Now, on p. 3074, Brian Hendrich and colleagues present a comprehensive analysis of the role of Sall4 in self-renewal and differentiation, and shed light on the nature of its interaction with the NuRD complex during these events. Using a series of phenotypical and transcriptional analyses of double Sall4/1 knockout mouse ESCs (mESCs), the authors show that Sall1 and Sall4 are dispensable for ESC pluripotency but are required to repress neuronal differentiation. Remarkably, the authors observed the spontaneous production of neurons alongside self-renewing mESCs in the double knockout mESCs. Genome-wide analyses demonstrate that, although a small proportion of Sall4 does indeed interact with NuRD, Sall4 neither recruits nor functions through the NuRD complex. Rather, Sall4 is seen to bind to enhancer sequences along with the pluripotency-associated transcription factors Pou5f1, Nanog, Klf4 and Esrrb, which can result in either gene activation or repression. Together, these data shed light on a number of previously unresolved issues with regard to the function of Sall4 in mammalian development.

The asymmetry of asynchrony: new roles for CYB-3 in cell division

Regulation of the cell cycle is a crucial component of development, and has been linked to the execution of cell fate decisions in a wide range of developmental contexts. Although many of the molecular components involved in cell cycle progression have been identified, how these proteins are regulated and how their distribution and abundance can influence cell fate remains unclear. In this issue (p. 3119), Matthew Michael identifies cyclin B3 (CYB-3) as a key regulator of cell cycle timing in the developing C. elegans embryo. Using RNAi to knockdown CYB-3, Michael demonstrates that in the one-cell embryo CYB-3 controls not only mitotic entry but S-phase entry as well – a dual-action that is unique among cyclins. At the two-cell stage, the author shows that CYB-3 is asymmetrically distributed in a par-dependant manner such that somatic precursor cells inherit ∼2.5-fold more CYB-3 than do their germline precursor sister cells. The author uses maternal strains with varying copy numbers of cyb-3 to show how variations in the level of CYB-3 can affect the speed and synchrony of the cell cycle at the two-cell stage, suggesting a novel role for CYB-3 in regulating asynchronous cell cycling in the developing embryo. Together, these data advance our understanding of how the timing of cell division is differentially regulated in the early embryo.

PLUS:

Introducing cross-referee commenting in peer review

Following our recent community survey on priorities in peer review and online publishing, we are making changes to the journal, including some changes to our peer review process. Find out more by reading the Editorial on p. 3035

Slit-Robo signaling

Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Here, Heike Blockus and Alain Chédotalsummarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation. See the Development at a Glance poster article on p. 3037

Metabolism meets development at Wiston House

It is becoming increasingly clear that cellular metabolite levels regulate the activity of signaling pathways, and conversely that signaling pathways affect cellular physiology and growth via metabolic pathways. Thus, metabolism and signaling mutually influence each other. The recent Company of Biologists’ Workshop ‘Metabolism in Development and Disease’ brought together people studying signaling and development with people studying metabolism, particularly in a cancer context. Here, Aurelio Teleman discusses examples of talks that illustrated this principle. See the Meeting Review on p. 3045

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

Phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) constitute the core components of the PI3K/AKT/mTOR signalling cascade, regulating cell proliferation, survival and metabolism. Although these functions are well-defined in the context of tumorigenesis, recent studies – in particular those using pluripotent stem cells – have highlighted the importance of this pathway to development and cellular differentiation. Here, Jason Yu and Wei Cui review the role PI3K/AKT/mTOR signalling plays in the control of pluripotency and differentiation, with a particular focus on the molecular mechanisms underlying these functions. See the Review on p. 3050

The roles of microRNAs and siRNAs in mammalian spermatogenesis

MicroRNAs and siRNAs, both of which are AGO-bound small RNAs, are essential for mammalian spermatogenesis. Although their precise germline roles remain largely uncharacterized, recent discoveries suggest that they function in mechanisms beyond microRNA-mediated post-transcriptional control, playing roles in DNA repair and transcriptional regulation within the nucleus. Here, Andrew Grimson and colleagues discuss the latest findings regarding roles for AGO proteins and their associated small RNAs in the male germline. They also evaluate the emerging and differing roles for AGOs and AGO-bound small RNAs in the male and female germlines, suggesting potential reasons for these sexual dimorphisms. See the Review on p. 3061

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