Binary Fate Research Articles

Evolution and final fate of massive post-common-envelope binaries

Mergers of neutron stars (NSs) and black holes (BHs) are nowadays observed routinely thanks to gravitational-wave (GW) astronomy. In the isolated binary-evolution channel, a common-envelope (CE) phase of a red supergiant (RSG) and a compact object is crucial to sufficiently shrink the orbit and thereby enable a merger via GW emission. Here, we use the outcomes of two three-dimensional (3D) magneto-hydrodynamic CE simulations of an initially 10.0 solar-mass RSG with a 5.0 solar-mass BH and a 1.4 solar-mass NS, respectively, to explore the further evolution and final fate of the remnant binaries (post-CE binaries). Notably, the 3D simulations reveal that the post-CE binaries are likely surrounded by circumbinary disks (CBDs), which contain substantial mass and angular momentum to influence the subsequent evolution. The binary systems in MESA modelling undergo another phase of mass transfer and we find that most donor stars do not explode in ultra-stripped supernovae (SNe), but rather in Type Ib/c SNe. Without NS kicks, the final orbital configurations of our models with the BH companion are too wide to allow for a compact object merger within a Hubble time. NS kicks are actually required to sufficiently perturb the orbit and thus facilitate a merger via GW emission. Moreover, we explore the influence of CBDs observed in 3D CE simulations on the evolution and final fate of the post-CE binaries. We find that mass accretion from the disk widens the binary orbit, while resonant interactions between the CBD and the binary can shrink the separation and increase the eccentricity of the binary depending on the disk mass and lifetime. Efficient resonant contractions may even enable a BH or NS to merge with the remnant He stars before a second SN explosion, which may be observed as gamma-ray burst-like transients, luminous fast blue optical transients, and Thorne-Żytkow objects. For the surviving post-CE binaries, the CBD-binary interactions may significantly increase the GW-induced double compact merger fraction. We conclude that accounting for CBD may be crucial to better understand observed GW mergers.

Abstract 2051: Monocyte Recruitment And Fate Specification Within Atherosclerotic Lesions

Recruited monocytes that subsequently differentiate into macrophages within atherosclerotic lesions are a primary driver of plaque progression and a risk factor for rupture. Advances in single cell RNA sequencing have expanded our understanding of macrophage diversity within plaques. However, limited analysis has explored regulators of monocyte lineage commitment and spatial localization in atherosclerotic plaque. Examining scRNAseq gene expression data of plaque-associated monocyte and macrophage lineages, pseudotime trajectory analysis predicted a binary fate decision by monocytes differentiating toward either an inflammatory or lipid-loaded “foamy” differentiation state. Foamy state was associated with lipid processing genes ( Fabp5, Lgals3, Trem2 ), whereas inflammatory state was associated with inflammasome genes ( Il1b, Nlrp3 ) and chemokines ( Ccl3, Ccl4 ). To test the in silico analysis, we established a monocyte fate mapping approach using a tamoxifen-inducible reporter mouse (CCR2 creERT2 Rosa26 lsl-tdTomato ) and performed kinetic analysis of tdTomato+ cells within plaque. tdTomato-labeled cells could be found shortly after tamoxifen treatment with small, rounded morphology, consistent with newly recruited monocytes. Within days, small, rounded cells were absent and labeled cells appeared to be lipid loaded with bloated morphology. Immunostaining revealed inflammasome activation in a large subset of monocytes immediately following recruitment to lesions. However, IL-1b hi cells were no longer detectable days after recruitment. Together, these data support a model where recruited monocytes commit toward either inflammatory or foamy lineage immediately upon plaque entry. Further, data support that inflammatory cells are short lived in atherosclerotic plaques, whereas foamy cells persist for longer periods of time. Ongoing work in our lab will address the role of known foamy macrophage regulators, including Trem2, in modulating fate commitment of monocytes entering early and late stage atherosclerotic lesions. Understanding the spatial-temporal dynamics of monocyte recruitment and differentiation will illuminate new mechanisms of atherosclerosis progression and potential therapeutic targets.

MicroRNA-124 directly suppresses Nodal and Notch to regulate mesodermal development

MicroRNAs regulate gene expression post-transcriptionally by destabilizing and/or inhibiting translation of target mRNAs in animal cells. MicroRNA-124 (miR-124) has been examined mostly in the context of neurogenesis. This study discovers a novel role of miR-124 in regulating mesodermal cell differentiation in the sea urchin embryo. The expression of miR-124 is first detectable at 12hours post fertilization at the early blastula stage, during endomesodermal specification. Mesodermally-derived immune cells come from the same progenitor cells that give rise to blastocoelar cells (BCs) and pigment cells (PCs) that must make a binary fate decision. We determined that miR-124 directly represses Nodal and Notch to regulate BC and PC differentiation. miR-124 inhibition does not impact the dorsal-ventral axis formation, but result in a significant increase in number of cells expressing BC-specific transcription factors (TFs) and a concurrent reduction of differentiated PCs. In general, removing miR-124's suppression of Nodal phenocopies miR124 inhibition. Interestingly, removing miR-124's suppression of Notch leads to an increased number of both BCs and PCs, with a subset of hybrid cells that express both BC- and PC-specific TFs in the larvae. Removal of miR-124's suppression of Notch not only affects differentiation of both BCs and PCs, but also induces cell proliferation of these cells during the first wave of Notch signaling. This study demonstrates that post-transcriptional regulation by miR-124 impacts differentiation of BCs and PCs by regulating the Nodal and Notch signaling pathways.

A bistable autoregulatory module in the developing embryo commits cells to binary expression fates.

Bistable autoactivation has been proposed as a mechanism for cells to adopt binary fates during embryonic development. However, it is unclear whether the autoactivating modules found within developmental gene regulatory networks are bistable, unless their parameters are quantitatively determined. Here, we combine invivo live imaging with mathematical modeling to dissect the binary cell fate dynamics of the fruit fly pair-rule gene fushi tarazu (ftz), which is regulated by two known enhancers: the early (non-autoregulating) element and the autoregulatory element. Live imaging of transcription and protein concentration in the blastoderm revealed that binary Ftz fates are achieved as Ftz expression rapidly transitions from being dictated by the early element to the autoregulatory element. Moreover, we discovered that Ftz concentration alone is insufficient to activate the autoregulatory element, and that this element only becomes responsive to Ftz at a prescribed developmental time. Based on these observations, we developed a dynamical systems model and quantitated its kinetic parameters directly from experimental measurements. Our model demonstrated that the ftz autoregulatory module is indeed bistable and that the early element transiently establishes the content of the binary cell fate decision to which the autoregulatory module then commits. Further in silico analysis revealed that the autoregulatory element locks the Ftz fate quickly, within 35min of exposure to the transient signal of the early element. Overall, our work confirms the widely held hypothesis that autoregulation can establish developmental fates through bistability and, most importantly, provides a framework for the quantitative dissection of cellular decision-making.

Blimp-1/PRDM1 and Hr3/RORβ specify the blue-sensitive photoreceptor subtype in Drosophila by repressing the hippo pathway.

During terminal differentiation of the mammalian retina, transcription factors control binary cell fate decisions that generate functionally distinct subtypes of photoreceptor neurons. For instance, Otx2 and RORβ activate the expression of the transcriptional repressor Blimp-1/PRDM1 that represses bipolar interneuron fate and promotes rod photoreceptor fate. Moreover, Otx2 and Crx promote expression of the nuclear receptor Nrl that promotes rod photoreceptor fate and represses cone photoreceptor fate. Mutations in these four transcription factors cause severe eye diseases such as retinitis pigmentosa. Here, we show that a post-mitotic binary fate decision in Drosophila color photoreceptor subtype specification requires ecdysone signaling and involves orthologs of these transcription factors: Drosophila Blimp-1/PRDM1 and Hr3/RORβ promote blue-sensitive (Rh5) photoreceptor fate and repress green-sensitive (Rh6) photoreceptor fate through the transcriptional repression of warts/LATS, the nexus of the phylogenetically conserved Hippo tumor suppressor pathway. Moreover, we identify a novel interaction between Blimp-1 and warts, whereby Blimp-1 represses a warts intronic enhancer in blue-sensitive photoreceptors and thereby gives rise to specific expression of warts in green-sensitive photoreceptors. Together, these results reveal that conserved transcriptional regulators play key roles in terminal cell fate decisions in both the Drosophila and the mammalian retina, and the mechanistic insights further deepen our understanding of how Hippo pathway signaling is repurposed to control photoreceptor fates for Drosophila color vision.

Notch-dependent binary fate choice regulates the Netrin pathway to control axon guidance of Drosophila visual projection neurons

Notch-dependent binary fate choice between sister neurons is one of the mechanisms to generate neural diversity. How these upstream neural fate specification programs regulate downstream effector genes to control axon targeting and neuropil assembly remains less well understood. Here, we report that Notch-dependent binary fate choice in Drosophila medulla neurons is required to regulate the Netrin axon guidance pathway, which controls targeting of transmedullary (Tm) neurons to lobula. In medulla neurons of Notch-on hemilineage composed of mostly lobula-targeting neurons, Notch signaling is required to activate theexpression of Netrin-B and repress the expression of its repulsive receptor Unc-5. Turning off Unc-5 is necessary for Tm neurons to target lobula. Furthermore, Netrin-B provided by Notch-on medulla neurons is required for correct targeting of Tm axons from later-generated medulla columns. Thus, the coordinate regulation of Netrin pathway components by Notch signaling ensures correct targeting of Tm axons and contributes to the neuropil assembly.

Binary Black Hole Formation with Detailed Modeling: Stable Mass Transfer Leads to Lower Merger Rates

Abstract Rapid binary population synthesis codes are often used to investigate the evolution of compact-object binaries. They typically rely on analytical fits of single-star evolutionary tracks and parameterized models for interactive phases of evolution (e.g., mass transfer on a thermal timescale, determination of dynamical instability, and common envelope) that are crucial to predict the fate of binaries. These processes can be more carefully implemented in stellar structure and evolution codes such as MESA. To assess the impact of such improvements, we compare binary black hole mergers as predicted in models with the rapid binary population synthesis code COSMIC to models ran with MESA simulations through mass transfer and common-envelope treatment. We find that results significantly differ in terms of formation paths, the orbital periods and mass ratios of merging binary black holes, and consequently merger rates. While common-envelope evolution is the dominant formation channel in COSMIC, stable mass transfer dominates in our MESA models. Depending upon the black hole donor mass, and mass-transfer and common-envelope physics, at subsolar metallicity, COSMIC overproduces the number of binary black hole mergers by factors of 2–35 with a significant fraction of them having merger times orders of magnitude shorter than the binary black holes formed when using detailed MESA models. Therefore we find that some binary black hole merger rate predictions from rapid population syntheses of isolated binaries may be overestimated by factors of ∼ 5–500. We conclude that the interpretation of gravitational-wave observations requires the use of detailed treatment of these interactive binary phases.

The ZO-1 protein Polychaetoid as an upstream regulator of the Hippo pathway in Drosophila.

The generation of a diversity of photoreceptor (PR) subtypes with different spectral sensitivities is essential for color vision in animals. In the Drosophila eye, the Hippo pathway has been implicated in blue- and green-sensitive PR subtype fate specification. Specifically, Hippo pathway activation promotes green-sensitive PR fate at the expense of blue-sensitive PRs. Here, using a sensitized triple heterozygote-based genetic screening approach, we report the identification of the single Drosophila zonula occludens-1 (ZO-1) protein Polychaetoid (Pyd) as a new regulator of the Hippo pathway during the blue- and green-sensitive PR subtype binary fate choice. We demonstrate that Pyd acts upstream of the core components and the upstream regulator Pez in the Hippo pathway. Furthermore, We found that Pyd represses the activity of Su(dx), a E3 ligase that negatively regulates Pez and can physically interact with Pyd, during PR subtype fate specification. Together, our results identify a new mechanism underlying the Hippo signaling pathway in post-mitotic neuronal fate specification.

GFI1B Splice Variants Differentially Regulate Transcription and Megakaryocyte/Erythrocyte Fate in Hematopoiesis

Alternative splicing is a powerful way to expand functional genetic diversity without increasing the number of genes. Recent deep sequencing efforts reveal that 100% of human genes are alternatively spliced. Alternative splicing is enriched in genes that control cell cycle dynamics, transcription and organelle organization during erythrocyte differentiation.Growth factor independence (GFI) 1B is comprised of an N-terminal SNAG domain, a C-terminal concatemer of six C2H2 zinc fingers (ZnFs), and a linker that joins them. GFI1B is required for both definitive erythropoiesis and megakaryopoiesis. Elevated GFI1B expression is seen in AML, while GFI1B mutations cause inherited platelet disorders. Understanding GFI1B function is critical to addressing its contributions to diseases of hematopoiesis. GFI1B has two splice variants, GFI1B-full and GFI1B-short . GFI1B-short lacks ZnFs 1 and 2, but is otherwise structurally identical to GFI1B-full. Both splice variants are expressed during erythroid differentiation from megakaryocyte-erythrocyte progenitors (MEPs), but their distinctive functions and relative contibutions to this binary fate decision remain largely unexplored.We used the bipotent, GFI1B-dependent erythroleukemia cell line, K562, to explore fate specifying and mechanistic differences between GFI1B-full and GFI1B-short. Inducible expression of GFI1B-full in K562 cells promotes spontaneous erythroid differentiation and antagonizes 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocyte differentiation. In contrast, GFI1B-short fails to support spontaneous erythroid differentiation and instead enables megakaryocyte fate in response to TPA. These findings suggest ZnFs 1 and 2 control fate-specifying differences between GFI1B splice variants. We have previously shown the GFI1B paralog, GFI1, is SUMOylated and that a portion of the linker region and ZnFs 1-3 provide binding surfaces for the E3 SUMO ligase, Protein Inhibitor of Activated STAT (PIAS)3. To gain additional insights regarding binding relationships between GFI1B and PIAS family proteins, we mapped the binding interface between GFI1B-full and PIAS3 and investigated binding differences between GFI1B-full vs. GFI1B-short for PIAS family members. We find ZnFs 1-3 of GFI1B are necessary and sufficient for PIAS3 binding and predicted impaired PIAS protein binding by GFI1B-short. While modest impairment was observed between GFI1B-short and PIAS proteins, PIASXa binding was completely abolished. We also find that GFI1B-full is SUMOylated on lysine (K)-61 within a yKXD/E SUMOylation consensus element. Yet, GFI1B-short is not SUMOylated, despite this consensus element being present. This suggests that differential recruitment of the SUMOylation machinery by GFI1 splice variants and assembly of distinct, SUMO-dependent transcriptional regulatory complexes may direct binary cell fate decisions. Using proximity-based in situ biotinylation and mass spectral analysis, we recorded the composition of transcriptional regulatory complexes assembled by GFI1B-full and GFI1B-short. We identifed candidate factors whose recruitment by GFI1B may be SUMOylation-dependent, suggesting that GFI1B splicing variation and differential SUMOylation may direct lineage allocation in hematopoiesis. DisclosuresNo relevant conflicts of interest to declare.

Orbital Evolution of Equal-mass Eccentric Binaries due to a Gas Disk: Eccentric Inspirals and Circular Outspirals

Abstract We solve the equations of two-dimensional hydrodynamics describing a circumbinary disk accreting onto an eccentric, equal-mass binary. We compute the time rate of change of the binary semimajor axis a and eccentricity e over a continuous range of eccentricities spanning e = 0 to e = 0.9. We find that binaries with initial eccentricities e 0 ≲ 0.1 tend to e = 0, where the binary semimajor axis expands. All others are attracted to e ≈ 0.4, where the binary semimajor axis decays. The e ≈ 0.4 attractor is caused by a rapid change in the disk response from a nearly origin-symmetric state to a precessing asymmetric state. The state change causes the time rates of change a ̇ and e ̇ to steeply change sign at the same critical eccentricity resulting in an attracting solution where a ̇ = e ̇ = 0 . This does not, however, result in a stalled, eccentric binary. The finite transition time between disk states causes the binary eccentricity to evolve beyond the attracting eccentricity in both directions resulting in oscillating orbital parameters and a drift of the semimajor axis. For the chosen disk parameters, binaries with e 0 ≳ 0.1 evolve toward and then oscillate around e ≈ 0.4 where they shrink in semimajor axis. Because unequal mass binaries grow toward equal mass through preferential accretion, our results are applicable to a wide range of initial binary mass ratios. Hence, these findings merit further investigations of this disk transition; understanding its dependence on disk parameters is vital for determining the fate of binaries undergoing orbital evolution with a circumbinary disk.

The Transcription Co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation Into Enterocyte vs Secretory Lineages

Background & AimsNotch signaling maintains intestinal stem cells (ISCs). When ISCs exit the niche, Notch signaling among early progenitor cells at position +4/5 regulates their specification toward secretory vs enterocyte lineages (binary fate). The transcription factor ATOH1 is repressed by Notch in ISCs; its de-repression, when Notch is inactivated, drives progenitor cells to differentiate along the secretory lineage. However, it is not clear what promotes transition of ISCs to progenitors and how this fate decision is established.MethodsWe sorted cells from Lgr5-GFP knockin intestines from mice and characterized gene expression patterns. We analyzed Notch regulation by examining expression profiles (by quantitative reverse transcription polymerase chain reaction and RNAscope) of small intestinal organoids incubated with the Notch inhibitor DAPT, intestine tissues from mice given injections of the γ-secretase inhibitor dibenzazepine, and mice with intestine-specific disruption of Rbpj. We analyzed intestine tissues from mice with disruption of the RUNX1 translocation partner 1 gene (Runx1t1, also called Mtg8) or CBFA2/RUNX1 partner transcriptional co-repressor 3 (Cbfa2t3, also called Mtg16), and derived their organoids, by histology, immunohistochemistry, and RNA sequencing (RNA-seq). We performed chromatin immunoprecipitation and sequencing analyses of intestinal crypts to identify genes regulated by MTG16.ResultsThe transcription co-repressors MTG8 and MTG16 were highly expressed by +4/5 early progenitors, compared with other cells along crypt-villus axis. Expression of MTG8 and MTG16 were repressed by Notch signaling via ATOH1 in organoids and intestine tissues from mice. MTG8- and MTG16-knockout intestines had increased crypt hyperproliferation and expansion of ISCs, but enterocyte differentiation was impaired, based on loss of enterocyte markers and functions. Chromatin immunoprecipitation and sequencing analyses showed that MTG16 bound to promoters of genes that are specifically expressed by stem cells (such as Lgr5 and Ascl2) and repressed their transcription. MTG16 also bound to previously reported enhancer regions of genes regulated by ATOH1, including genes that encode Delta-like canonical Notch ligand and other secretory-specific transcription factors.ConclusionsIn intestine tissues of mice and human intestinal organoids, MTG8 and MTG16 repress transcription in the earliest progenitor cells to promote exit of ISCs from their niche (niche exit) and control the binary fate decision (secretory vs enterocyte lineage) by repressing genes regulated by ATOH1.

Different modes of Notch activation and strength regulation in the spermathecal secretory lineage.

The strength of Notch signaling contributes to pleiotropic actions of Notch; however, we do not yet have a full understanding of the molecular regulation of Notch-signaling strength. We have investigated the mode of Notch activation in binary fate specification in the Drosophila spermathecal linage, where Notch is asymmetrically activated across three divisions to specify different cell fates. Using clonal analysis, we show that Delta (Dl) serves as the ligand for Notch in the first and second divisions. Dl and Serrate (Ser) function redundantly in the third division. Compared with the third division, cell-fate decision in the second division requires a lower level of Suppressor of Hairless protein, and, consequently, a lower level of Notch signaling. Several Notch endosomal trafficking regulators differentially regulate Notch signaling between the second and third divisions. Here, we demonstrate that cell differentiation in spermathecae involves different Notch-activation modes, Notch-signaling strengths and Notch-trafficking regulations. Thus, the Drosophila spermathecal lineage is an exciting model for probing the molecular mechanisms that modulate the Notch signaling pathway.

Binary Fate Choice between Closely Related Interneuronal Types Is Determined by a Fezf1-Dependent Postmitotic Transcriptional Switch

Many neuronal types occur as pairs that are similar in most respects but differ in a key feature. In some pairs of retinal neurons, called paramorphic, one member responds to increases and the other to decreases in luminance (ON and OFF responses). Here, we focused on one such pair, starburst amacrine cells (SACs), to explore how closely related neuronal types diversify. We find that ON and OFF SACs are transcriptionally distinct prior to their segregation, dendritic outgrowth, and synapse formation. The transcriptional repressor Fezf1 is selectively expressed by postmitotic ON SACs and promotes the ON fate and gene expression program while repressing the OFF fate and program. The atypical Rho GTPase Rnd3 is selectively expressed by OFF SACs and regulates their migration but is repressed by Fezf1 in ON SACs, enabling differential positioning of the two types. These results define a transcriptional program that controls diversification of a paramorphic pair.

Notch pathway: a bistable inducer of biological noise?

Notch signalling pathway is central to development of metazoans. The pathway codes a binary fate switch. Upon activation, downstream signals contribute to resolution of fate dichotomies such as proliferation/differentiation or sub-lineage differentiation outcome. There is, however, an interesting paradox in the Notch signalling pathway. Despite remarkable predictability of fate outcomes instructed by the Notch pathway, the associated transcriptome is versatile and plastic. This inconsistency suggests the presence of an interface that compiles input from the plastic transcriptome of the Notch pathway but communicates only a binary output in biological decisions. Herein, we address the interface that determines fate outcomes. We provide an alternative hypothesis for the Notch pathway as a biological master switch that operates by induction of genetic noise and bistability in order to facilitate resolution of dichotomous fate outcomes in development.Graphical abstract

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex.

Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B's obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.

The Fate of Binaries in the Galactic Center: The Mundane and the Exotic

Abstract The Galactic center is dominated by the gravity of a super-massive black hole (SMBH), Sagittarius A*, and is suspected to contain a sizable population of binary stars. Such binaries form hierarchical triples with the SMBH, undergoing Eccentric Kozai–Lidov (EKL) evolution, which can lead to high-eccentricity excitations for the binary companions’ mutual orbit. This effect can lead to stellar collisions or Roche-lobe crossings, as well as orbital shrinking due to tidal dissipation. In this work we investigate the dynamical and stellar evolution of such binary systems, especially with regards to the binaries’ post-main-sequence evolution. We find that the majority of binaries (∼75%) is eventually separated into single stars, while the remaining binaries (∼25%) undergo phases of common-envelope evolution and/or stellar mergers. These objects can produce a number of different exotic outcomes, including rejuvenated stars, G2-like infrared-excess objects, stripped giant stars, Type Ia supernovae (SNe), cataclysmic variables, symbiotic binaries, or compact object binaries. We estimate that, within a sphere of 250 Mpc radius, about 7.5–15 SNe Ia per year should occur in galactic nuclei due to this mechanism, potentially detectable by the Zwicky Transient Facility and ASAS-SN. Likewise, we estimate that, within a sphere of 1 Gpc3 volume, about 10–20 compact object binaries form per year that could become gravitational wave sources. Based on results of EKL-driven compact object binary mergers in galactic nuclei by Hoang et al., this compact object binary formation rate translates to about 15–30 events per year that are detectable by Advanced LIGO.

Direct control of somatic stem cell proliferation factors by the Drosophila testis stem cell niche.

Niches have traditionally been characterised as signalling microenvironments that allow stem cells to maintain their fate. This definition implicitly assumes that the various niche signals are integrated towards a binary fate decision between stemness and differentiation. However, observations in multiple systems have demonstrated that stem cell properties, such as proliferation and self-renewal, can be uncoupled at the level of niche signalling input, which is incompatible with this simplified view. We have studied the role of the transcriptional regulator Zfh1, a shared target of the Hedgehog and Jak/Stat niche signalling pathways, in the somatic stem cells of the Drosophila testis. We found that Zfh1 binds and downregulates salvador and kibra, two tumour suppressor genes of the Hippo/Wts/Yki pathway, thereby restricting Yki activation and proliferation to the Zfh1+ stem cells. These observations provide an unbroken link from niche signal input to an individual aspect of stem cell behaviour that does not, at any step, involve a fate decision. We discuss the relevance of these findings for an overall concept of stemness and niche function.

Asynchronous lineage priming determines commitment to T cell and B cell lineages in fetal liver.

The molecular events that initiate lymphoid-lineage specification remain unidentified because the stages of differentiation during which lineage commitment occurs are difficult to characterize. We isolated fetal liver progenitor cells undergoing restriction of their differentiation potential toward the T cell-innate lymphoid cell lineage or the B cell lineage. Transcripts that defined the molecular signatures of these two subsets were sequentially upregulated in lympho-myeloid precursor cells and in common lymphoid progenitor cells, respectively, and this preceded lineage restriction; this indicates that T cell-versus-B cell commitment is not a binary fate 'decision'. The T cell-bias and B cell-bias transcriptional programs were frequently co-expressed in common lymphoid progenitor cells and were segregated in subsets biased toward T cell differentiation or B cell differentiation, after interleukin 7 (IL-7) signaling that controlled the number of progenitor cells engaging in T cell differentiation versus B cell differentiation.

Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells

Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood. More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation invivo are lacking. In Drosophila pupae, Notch signals during cytokinesis to regulate the intra-lineage pIIa/pIIb decision in the sensory organ lineage. Here, we identify two pools of Notch along the pIIa-pIIb interface, apical and basal to the midbody. Analysis of the dynamics of Notch, Delta, and Neuralized distribution in living pupae suggests that ligand endocytosis and receptor activation occur basal to the midbody. Using selective photo-bleaching of GFP-tagged Notch and photo-tracking of photo-convertible Notch, we show that nuclear Notch is indeed produced by receptors located basal to the midbody. Thus, only a specific subset of receptors, located basal to the midbody, contributes to signaling in pIIa. This is the first invivo characterization of the pool of Notch contributing to signaling. We propose a simple mechanism of cell fate decision based onintra-lineage signaling: ligands and receptors localize during cytokinesis to the new cell-cell interface, thereby ensuring signaling between sister cells, hence intra-lineage fate decision.

Rapid and Bright Stellar-mass Binary Black Hole Mergers in Active Galactic Nuclei

Abstract The Laser Interferometer Gravitational-wave Observatory (LIGO) found direct evidence for double black hole binaries emitting gravitational waves. Galactic nuclei are expected to harbor the densest population of stellar-mass black holes. A significant fraction ( ) of these black holes can reside in binaries. We examine the fate of the black hole binaries in active galactic nuclei, which get trapped in the inner region of the accretion disk around the central supermassive black hole. We show that binary black holes can migrate into and then rapidly merge within the disk well within a Salpeter time. The binaries may also accrete a significant amount of gas from the disk, well above the Eddington rate. This could lead to detectable X-ray or gamma-ray emission, but would require hyper-Eddington accretion with a few percent radiative efficiency, comparable to thin disks. We discuss implications for gravitational-wave observations and black hole population studies. We estimate that Advanced LIGO may detect ∼20 such gas-induced binary mergers per year.