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Key Points During development, cells become progressively restricted in their lineage choices. The allocation of cells to a specific lineage is regulated by the activities of key signalling pathways and developmentally regulated transcription factors. The first binary cell lineage decision, between the trophectoderm (TE) and the inner cell mass (ICM), is governed by the exclusive expression of caudal-type homeobox protein 2 (CDX2) and octamere-binding transcription factor 3/4 (OCT3/4; also known as POU5F1) in TE or ICM, respectively. The ICM is further subdivided into the primitive endoderm and epiblast by expression of GATA-binding factor 6 (GATA6) and nanog. Signals from the extraembryonic tissues, namely the TE and primitive endoderm, have instructive roles in setting up the embryonic axes and are the source of growth factors and their antagonists that regulate cell type specification in epiblast derivatives during gastrulation. The primitive streak is the site where the mesoderm and definitive endoderm are formed and it is induced in response to Wnt and transforming growth factor β (TGFβ)–nodal signalling. At the primitive streak, cells are allocated to specific fates according to their spatio-temporal position in the streak. The positional information reflects differences in signalling strength of fibroblast growth factor 8 (FGF8), WNT3 or WNT3A and nodal–SMAD2 and SMAD3 and bone morphogenetic protein 4 (BMP4), which are integrated to direct cell lineage specification and regulate morphogenesis. Segregation of primordial germ cells (PGCs) from the somatic lineages at gastrulation requires BMP4–SMAD1 and SMAD5 signals from the extraembryonic ectoderm. Primordial germ cells undergo extensive epigenetic reprogramming to maintain pluripotency throughout the life cycle. Genetic studies combined with in vivo imaging analysis have identified signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. These mechanisms are also conserved in lower vertebrates. Genetic studies have identified the key signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. Recent advances have uncovered details of the molecular circuits that tightly control cell growth and differentiation in the mammalian embryo from the blastocyst stage, through the establishment of initial anterior–posterior polarity, to gastrulation, when the germ cells are set aside and the three primary germ layers are specified. Relevant studies in lower vertebrates indicate the conservation and divergence of regulatory mechanisms for cell lineage allocation and axis patterning.

Direct reprogramming by forced expression of transcription factors can convert one cell type into another. Thus, desired cell types can be generated bypassing pluripotency. However, direct reprogramming towards renal cells remains an unmet challenge. Here, we identify renal cell fate-inducing factors on the basis of their tissue specificity and evolutionarily conserved expression, and demonstrate that combined expression of Emx2 , Hnf1b , Hnf4a and Pax8 converts mouse and human fibroblasts into induced renal tubular epithelial cells (iRECs). iRECs exhibit epithelial features, a global gene expression profile resembling their native counterparts, functional properties of differentiated renal tubule cells and sensitivity to nephrotoxic substances. Furthermore, iRECs integrate into kidney organoids and form tubules in decellularized kidneys. Our approach demonstrates that reprogramming factors can be identified by targeted in silico analysis. Renal tubular epithelial cells generated ex vivo by forced expression of transcription factors may facilitate disease modelling, drug and nephrotoxicity testing, and regenerative approaches. Kaminski  et al.  demonstrate that combined expression of the transcription factors Emx2, Hnf1b, Hnf4a and Pax8 converts mouse and human fibroblasts into induced renal tubular epithelial cells.

During aging, peripheral nerves undergo structural and cellular changes that trigger loss of function, impair quality of life, and increase disease risk. During peripheral nerve aging there are cellular and molecular changes, such as increased extracellular matrix deposition. The mechanisms behind these aging-induced alterations remain unclear. Here, we profile mouse sciatic nerves using single nucleus transcriptomics and unravel changes in macrophage subtypes during nerve aging. Phagocytic macrophage numbers increase at the onset of aging, followed by higher numbers of chronic inflammatory macrophages. Based on ligand-receptor analysis, we predict that increased fibroblast growth factor (FGF) signaling from adipocytes activates a chondrocyte-like neural fibroblast state during peripheral nerve aging. Finally, we show that FGF2 induces the co-expression of the chondrocyte markers SOX9 and FOXC2 in senescent human perineurial fibroblast, that can be blocked with FGF1. In conclusion, our findings reveal some of the molecular mechanisms of peripheral nerve aging by FGF-regulated induction of a chondrocyte-like fibroblast state. Peripheral nerve aging involves structural changes and extracellular matrix deposition. Here, the authors show peripheral nerve cell population shifts and induction of a chondrocyte-like fibroblast state through fibroblast growth factor signaling during aging.

The cerebral cortex contains multiple areas with distinctive cytoarchitectonic patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modeling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas. Recognizable by its deep outer folds in humans, the cerebral cortex is a region of the mammalian brain which handles complex processes such as conscious perception or decision-making. It is organized in several layers that contain different types of ‘excitatory’ neurons which can activate other cells. The various areas of the cortex have different characteristics as they contain various proportions of each kind of neurons. Stem cells are cells capable to divide and create various types of specialized cells. The excitatory neurons in the cortex are created during development by stem cells known as radial glial cells. These cells divide several times, giving rise to different types of neurons in sucessive divisions, presumably thanks to internal molecular clocks. In the cortex, it is generally assumed that an individual radial glial cell produces all the different types of excitatory neurons. However, studies have suggested that certain cells could be specialized in creating specific types of neurons. To explore this question, Llorca et al. used three complementary approaches to follow individual radial glial cells and track the neurons they created in mouse embryos. This helped to understand how groups of stem cells work together to build the cortex. The experiments revealed that radial glial cells differ more than anticipated in the number and the types of neurons they generate, and rarely produce all types of excitatory neurons. In other words, the output of individual radial glial cells is not always the same. The results by Llorca et al. suggest that as radial glial cells divide, they undergo a series of probabilistic decisions – that is, in each division the cells have a certain probability to generate a specific type of neuron. Consequently, the resulting lineages are rarely identical or contain all types of excitatory neurons, but collectively they generate the full diversity of excitatory neurons in the cortex. Ultimately, new insights into how excitatory neurons form and connect in the brain may be used to help understand psychiatric conditions where circuits in the cortex might be impaired, such as in autism spectrum disorders.

The functional role of adult neurogenesis in the hippocampus remains the subject of intense speculation. One recent hypothesis is that adult-born neurons contribute to the endocrine and behavioural outputs of the stress response. Here we show a genetic model system to ablate neurogenesis by inducibly deleting Tbr2 gene function specifically in the hippocampus and corroborate our findings in a radiation-based model of neurogenesis deprivation. We found that mice with ablation of new neurons in the dentate gyrus exhibit reduced anxiety during the dark cycle. After restraint stress, corticosterone levels in neurogenesis-deficient mice decreased more quickly than controls and were more sensitive to suppression by dexamethasone. Furthermore, glucocorticoid receptor target genes and neuronal activity markers showed reduced expression after stress in neurogenesis-deficient mice. These findings suggest that newborn neurons in the hippocampus are involved in sensing and eliciting an appropriate response to stress. Adult hippocampal neurogenesis is involved in the response to stress but whether it exerts a positive or negative effect remains unclear. Here the authors ablate hippocampal neurogenesis in mice and find that the effects on anxiety behaviour depend on the time of day, and that neurogenesis specifically impairs the response to stress during the dark cycle.

The T-box transcription factors T-bet and Eomesodermin regulate type 1 immune responses in innate and adaptive lymphocytes. T-bet is widely expressed in the immune system but was initially identified as the lineage-specifying transcription factor of Th1 CD4 + T cells, where it governs expression of the signature cytokine IFN- γ and represses alternative cell fates like Th2 and Th17. T-bet’s paralog Eomes is less abundantly expressed and Eomes + CD4 + T cells are mostly found in the context of persistent antigen exposure, like bone marrow transplantation, chronic infection or inflammation as well as malignant disorders. However, it has remained unresolved whether Eomes executes similar transcriptional activities as T-bet in CD4 + T cells. Here we use a novel genetic approach to show that Eomes expression in CD4 + T cells drives a distinct transcriptional program that shows only partial overlap with T-bet. We found that Eomes is sufficient to induce the expression of the immunoregulatory cytokine IL-10 and, together with T-bet, promotes a cytotoxic effector profile, including Prf1 , Gzmb , Gzmk , Nkg7 and Ccl5 , while repressing alternative cell fates. Our results demonstrate that Eomes + CD4 + T cells, which are often found in the context of chronic antigen stimulation, are likely to be a unique CD4 + T cell subset that limits inflammation and immunopathology as well as eliminates antigen-presenting and malignant cells.

The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize genetically defined progenitor subpopulations in live slices across key stages of mouse DG development, testing decades old static models of DG formation with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations, timings, dynamic cell-cell interactions, signaling activities, and routes underlie mosaic DG formation. Intermediate progenitors (IPs, Tbr2+) pioneered migrations, supporting and guiding later emigrating NSCs (Sox9+) through multiple transient zones prior to converging at the nascent outer adult niche in a dynamic settling process, generating all prenatal and postnatal granule neurons in defined spatiotemporal order. IPs (Dll1+) extensively targeted contacts to mitotic NSCs (Notch active), revealing a substrate for cell-cell contact support during migrations, a developmental feature maintained in adults. Mouse DG formation shares conserved features of human neocortical expansion.

The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for T-bet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections.

Retinal ganglion cells expressing the photopigment melanopsin are intrinsically photosensitive (ipRGCs). ipRGCs regulate subconscious non-image-forming behaviors such as circadian rhythms, pupil dilation, and light-mediated mood. Previously, we and others showed that the transcription factor Tbr2 (EOMES) is required during retinal development for the formation of ipRGCs. Tbr2 is also expressed in the adult retina leading to the hypothesis that it plays a role in adult ipRGC function. To test this, we removed Tbr2 in adult mice. We found that this results in the loss of melanopsin expression in ipRGCs but does not lead to cell death or morphological changes to their dendritic or axonal termination patterns. Additionally, we found ectopic expression of Tbr2 in conventional RGCs does not induce melanopsin expression but can increase melanopsin expression in existing ipRGCs. An interesting feature of ipRGCs is their superior survival relative to conventional RGCs after an optic nerve injury. We find that loss of Tbr2 decreases the survival rate of ipRGCs after optic nerve damage suggesting that Tbr2 plays a role in ipRGC survival after injury. Lastly, we show that the GABAergic amacrine cell marker Meis2, is expressed in the majority of Tbr2-expressing displaced amacrine cells as well as in a subset of Tbr2-expressing RGCs. These findings demonstrate that Tbr2 is necessary but not sufficient for melanopsin expression, that Tbr2 is involved in ipRGC survival after optic nerve injury, and identify a marker for Tbr2-expressing displaced amacrine cells.

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122 + CD49b + cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122 + CD49b + cells remain confined to a NK1.1 low NKp46 low stage, but differentiate into NK1.1 + NKp46 + cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling. Natural killer homeostasis is thought to be governed by gamma chain cytokines including IL-15. Here, the authors show that IL-12 can trigger the development of a distinct subset of natural killer cells with anti-tumour activity.