Carbon dynamics of mature and regrowth tropical forests derived from a pantropical database (TropForC‐db)

Tropical forests play a critical role in the global carbon (C) cycle, storing ~45% of terrestrial C and constituting the largest component of the terrestrial C sink. Despite their central importance to the global C cycle, their ecosystem‐level C cycles are not as well‐characterized as those of extra‐tropical forests, and knowledge gaps hamper efforts to quantify C budgets across the tropics and to model tropical forest‐climate interactions. To advance understanding of C dynamics of pantropical forests, we compiled a new database, the Tropical Forest C database (TropForC‐db), which contains data on ground‐based measurements of ecosystem‐level C stocks and annual fluxes along with disturbance history. This database currently contains 3568 records from 845 plots in 178 geographically distinct areas, making it the largest and most comprehensive database of its type. Using TropForC‐db, we characterized C stocks and fluxes for young, intermediate‐aged, and mature forests. Relative to existing C budgets of extra‐tropical forests, mature tropical broadleaf evergreen forests had substantially higher gross primary productivity (GPP) and ecosystem respiration (R_eco), their autotropic respiration (R_a) consumed a larger proportion (~67%) of GPP, and their woody stem growth (ANPP_stem) represented a smaller proportion of net primary productivity (NPP, ~32%) or GPP (~9%). In regrowth stands, aboveground biomass increased rapidly during the first 20 years following stand‐clearing disturbance, with slower accumulation following agriculture and in deciduous forests, and continued to accumulate at a slower pace in forests aged 20–100 years. Most other C stocks likewise increased with stand age, while potential to describe age trends in C fluxes was generally data‐limited. We expect that TropForC‐db will prove useful for model evaluation and for quantifying the contribution of forests to the global C cycle. The database version associated with this publication is archived in Dryad (DOI: 10.5061/dryad.t516f ) and a dynamic version is maintained at https://github.com/forc-db .     

Beyond the fast–slow continuum: demographic dimensions structuring a tropical tree community

Life‐history theory posits that trade‐offs between demographic rates constrain the range of viable life‐history strategies. For coexisting tropical tree species, the best established demographic trade‐off is the growth‐survival trade‐off. However, we know surprisingly little about co‐variation of growth and survival with measures of reproduction. We analysed demographic rates from seed to adult of 282 co‐occurring tropical tree and shrub species, including measures of reproduction and accounting for ontogeny. Besides the well‐established fast–slow continuum, we identified a second major dimension of demographic variation: a trade‐off between recruitment and seedling performance vs. growth and survival of larger individuals (≥ 1 cm dbh) corresponding to a ‘stature–recruitment’ axis. The two demographic dimensions were almost perfectly aligned with two independent trait dimensions (shade tolerance and size). Our results complement recent analyses of plant life‐history variation at the global scale and reveal that demographic trade‐offs along multiple axes act to structure local communities.     

Quantifying above‐ and belowground biomass carbon loss with forest conversion in tropical lowlands of Sumatra (Indonesia)

Natural forests in South‐East Asia have been extensively converted into other land‐use systems in the past decades and still show high deforestation rates. Historically, lowland forests have been converted into rubber forests, but more recently, the dominant conversion is into oil palm plantations. While it is expected that the large‐scale conversion has strong effects on the carbon cycle, detailed studies quantifying carbon pools and total net primary production (NPP_total) in above‐ and belowground tree biomass in land‐use systems replacing rainforest (incl. oil palm plantations) are rare so far. We measured above‐ and belowground carbon pools in tree biomass together with NPP_total in natural old‐growth forests, ‘jungle rubber’ agroforests under natural tree cover, and rubber and oil palm monocultures in Sumatra. In total, 32 stands (eight plot replicates per land‐use system) were studied in two different regions. Total tree biomass in the natural forest (mean: 384 Mg ha^?1) was more than two times higher than in jungle rubber stands (147 Mg ha^?1) and >four times higher than in monoculture rubber and oil palm plantations (78 and 50 Mg ha^?1). NPP_total was higher in the natural forest (24 Mg ha^?1 yr^?1) than in the rubber systems (20 and 15 Mg ha^?1 yr^?1), but was highest in the oil palm system (33 Mg ha^?1 yr^?1) due to very high fruit production (15–20 Mg ha^?1 yr^?1). NPP_total was dominated in all systems by aboveground production, but belowground productivity was significantly higher in the natural forest and jungle rubber than in plantations. We conclude that conversion of natural lowland forest into different agricultural systems leads to a strong reduction not only in the biomass carbon pool (up to 166 Mg C ha^?1) but also in carbon sequestration as carbon residence time (i.e. biomass‐C:NPP‐C) was 3–10 times higher in the natural forest than in rubber and oil palm plantations.     

Modeling and empirical validation of long‐term carbon sequestration in forests (France, 1850–2015)

The development of appropriate tools to quantify long‐term carbon (C) budgets following forest transitions, that is, shifts from deforestation to afforestation, and to identify their drivers are key issues for forging sustainable land‐based climate‐change mitigation strategies. Here, we develop a new modeling approach, CRAFT (CaRbon Accumulation in ForesTs) based on widely available input data to study the C dynamics in French forests at the regional scale from 1850 to 2015. The model is composed of two interconnected modules which integrate biomass stocks and flows (Module 1) with litter and soil organic C (Module 2) and build upon previously established coupled climate‐vegetation models. Our model allows to develop a comprehensive understanding of forest C dynamics by systematically depicting the integrated impact of environmental changes and land use. Model outputs were compared to empirical data of C stocks in forest biomass and soils, available for recent decades from inventories, and to a long‐term simulation using a bookkeeping model. The CRAFT model reliably simulates the C dynamics during France's forest transition and reproduces C‐fluxes and stocks reported in the forest and soil inventories, in contrast to a widely used bookkeeping model which strictly only depicts C‐fluxes due to wood extraction. Model results show that like in several other industrialized countries, a sharp increase in forest biomass and SOC stocks resulted from forest area expansion and, especially after 1960, from tree growth resulting in vegetation thickening (on average 7.8 Mt C/year over the whole period). The difference between the bookkeeping model, 0.3 Mt C/year in 1850 and 21 Mt C/year in 2015, can be attributed to environmental and land management changes. The CRAFT model opens new grounds for better quantifying long‐term forest C dynamics and investigating the relative effects of land use, land management, and environmental change.     

Long‐term recovery of the functional community assembly and carbon pools in an African tropical forest succession

On the African continent, the population is expected to expand fourfold in the next century, which will increasingly impact the global carbon cycle and biodiversity conservation. Therefore, it is of vital importance to understand how carbon stocks and community assembly recover after slash‐and‐burn events in tropical second growth forests. We inventoried a chronosequence of 15 1‐ha plots in lowland tropical forest of the central Congo Basin and evaluated changes in aboveground and soil organic carbon stocks and in tree species diversity, functional composition, and community‐weighted functional traits with succession. We aimed to track long‐term recovery trajectories of species and carbon stocks in secondary forests, comparing 5 to 200 + year old secondary forest with reference primary forest. Along the successional gradient, the functional composition followed a trajectory from resource acquisition to resource conservation, except for nitrogen‐related leaf traits. Despite a fast, initial recovery of species diversity and functional composition, there were still important structural and carbon stock differences between old growth secondary and pristine forest, which suggests that a full recovery of secondary forests might take much longer than currently shown. As such, the aboveground carbon stocks of 200 + year old forest were only 57% of those in the pristine reference forest, which suggests a slow recovery of aboveground carbon stocks, although more research is needed to confirm this observation. The results of this study highlight the need for more in‐depth studies on forest recovery in Central Africa, to gain insight into the processes that control biodiversity and carbon stock recovery.     

A joint individual‐based model coupling growth and mortality reveals that tree vigor is a key component of tropical forest dynamics

Tree vigor is often used as a covariate when tree mortality is predicted from tree growth in tropical forest dynamic models, but it is rarely explicitly accounted for in a coherent modeling framework. We quantify tree vigor at the individual tree level, based on the difference between expected and observed growth. The available methods to join nonlinear tree growth and mortality processes are not commonly used by forest ecologists so that we develop an inference methodology based on an MCMC approach, allowing us to sample the parameters of the growth and mortality model according to their posterior distribution using the joint model likelihood. We apply our framework to a set of data on the 20‐year dynamics of a forest in Paracou, French Guiana, taking advantage of functional trait‐based growth and mortality models already developed independently. Our results showed that growth and mortality are intimately linked and that the vigor estimator is an essential predictor of mortality, highlighting that trees growing more than expected have a far lower probability of dying. Our joint model methodology is sufficiently generic to be used to join two longitudinal and punctual linked processes and thus may be applied to a wide range of growth and mortality models. In the context of global changes, such joint models are urgently needed in tropical forests to analyze, and then predict, the effects of the ongoing changes on the tree dynamics in hyperdiverse tropical forests.     

Changes in the structure and function of northern Alaskan ecosystems when considering variable leaf‐out times across groupings of species in a dynamic vegetation model

The phenology of arctic ecosystems is driven primarily by abiotic forces, with temperature acting as the main determinant of growing season onset and leaf budburst in the spring. However, while the plant species in arctic ecosystems require differing amounts of accumulated heat for leaf‐out, dynamic vegetation models simulated over regional to global scales typically assume some average leaf‐out for all of the species within an ecosystem. Here, we make use of air temperature records and observations of spring leaf phenology collected across dominant groupings of species (dwarf birch shrubs, willow shrubs, other deciduous shrubs, grasses, sedges, and forbs) in arctic and boreal ecosystems in Alaska. We then parameterize a dynamic vegetation model based on these data for four types of tundra ecosystems (heath tundra, shrub tundra, wet sedge tundra, and tussock tundra), as well as ecotonal boreal white spruce forest, and perform model simulations for the years 1970–2100. Over the course of the model simulations, we found changes in ecosystem composition under this new phenology algorithm compared with simulations with the previous phenology algorithm. These changes were the result of the differential timing of leaf‐out, as well as the ability for the groupings of species to compete for nitrogen and light availability. Regionally, there were differences in the trends of the carbon pools and fluxes between the new phenology algorithm and the previous phenology algorithm, although these differences depended on the future climate scenario. These findings indicate the importance of leaf phenology data collection by species and across the various ecosystem types within the highly heterogeneous Arctic landscape, and that dynamic vegetation models should consider variation in leaf‐out by groupings of species within these ecosystems to make more accurate projections of future plant distributions and carbon cycling in Arctic regions.     

Central insulin‐like growth factor‐1 (IGF‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF‐1 decline

Low insulin‐like growth factor‐1 (IGF‐1) signaling is associated with improved longevity, but is paradoxically linked with several age‐related diseases in humans. Insulin‐like growth factor‐1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF‐1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole‐body insulin action in aging. Utilizing hyperinsulinemic‐euglycemic clamps, we show that old insulin‐resistant rats with age‐related declines in IGF‐1 level demonstrate markedly improved whole‐body insulin action, when treated with central IGF‐1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF‐1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF‐1 action in the brain and periphery provides a ‘balance’ between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at ‘tipping the balance’ of IGF‐1 action centrally are the optimal approach to achieve healthy aging and longevity in humans.     

Flowering and fruiting phenology of Normanbya normanbyi (W. Hill) L. H. Bailey (Arecaceae), a palm endemic to the lowland tropical rainforest of north‐eastern Australia

Abstract Normanbya normanbyi (W. Hill) L. H. Bailey (Arecaceae) is a monoecious, arborescent palm with a very small distribution area within the Daintree rainforest in north‐eastern Australia. Our 2‐year study was focused on the reproductive phenology at the individual and population level. At the population level flowering peaked in the dry season, whereas fruiting was confined to the wet season. Each palm can bear up to three inflorescences/infructescences at the same time. Flowering of each inflorescence is separated from each other by a couple of weeks. A single inflorescence consists of about 1900 staminate and 800 pistillate flowers. The flowering of N. normanbyi is protandrous with a staminate phase lasting 40 days and a pistillate phase of approximately 2 weeks. Between both phases is a non‐flowering phase of about 9 days. Fruit ripening takes 21 weeks, with an average of about 280 ripe fruit per tree. Comparison of three study plots revealed a moderate synchrony of flowering and fruiting initiation in this species of palm. The male phase of flowering shows a higher degree of synchrony than the female phase at the population level. Seasonal regularity of flowering and fruiting peaks appears to be predictable. The general flowering and fruiting phenology of N. normanbyi follows a subannual pattern with a strong tendency towards a continual pattern.     

Cloning,Expression and Characterization of the δ‐carbonic Anhydrase of Thalassiosira weissflogii (Bacillariophyceae)

Carbonic anhydrase (CA) is a ubiquitous metalloenzyme responsible for accelerating the interconversion of CO₂ and bicarbonate. Although CAs are involved in a broad range of biochemical processes involving carboxylation or decarboxylation reactions, they are of special interest due to their role in photosynthetic CO₂ assimilation in marine phytoplankton, especially under low‐CO₂ conditions. Several phylogenetically independent classes of CAs have been identified in a variety of marine phytoplankton. TWCA1, first discovered in Thalassiosira weissflogii (Grunow) G. Fryxell & Hasle, is the founding member of the δ‐class of CAs; these appear to be extracellular enzymes, but are still relatively poorly characterized. To date, it has remained uncertain whether TWCA1 possesses true CA activity due to the difficulty in producing a functional protein in a heterologous expression system. Herein we describe the fusion of a full‐length open reading frame of TWCA1 to the coding sequence of a self‐splicing intein in a pTWIN2 expression vector that has allowed successful production of a functional enzyme in Escherichia coli. Assay of the recombinant protein shows that TWCA1 is a catalytically active δ‐CA possessing both CO₂ hydration and esterase activity.     

Investigating the biochar effects on C‐mineralization and sequestration of carbon in soil compared with conventional amendments using the stable isotope (δ13C) approach

Biomass‐derived black carbon (biochar) is considered to be an effective tool to mitigate global warming by long‐term C‐sequestration in soil and to influence C‐mineralization via priming effects. However, the underlying mechanism of biochar (BC) priming relative to conventional biowaste (BW) amendments remains uncertain. Here, we used a stable carbon isotope (δ¹³C) approach to estimate the possible biochar effects on native soil C‐mineralization compared with various BW additions and potential carbon sequestration. The results show that immediately after application, BC suppresses and then increases C‐mineralization, causing a loss of 0.14–7.17 mg‐CO₂–C g^?1‐C compared to the control (0.24–1.86 mg‐CO₂–C g^?1‐C) over 1–120 days. Negative priming was observed for BC compared to various BW amendments (?10.22 to ?23.56 mg‐CO₂–C g^?1‐soil‐C); however, it was trivially positive relative to that of the control (8.64 mg‐CO₂–C g^?1‐soil‐C). Furthermore, according to the residual carbon and δ¹³C signature of postexperimental soil carbon, BC‐C significantly increased (P < 0.05) the soil carbon stock by carbon sequestration in soil compared with various biowaste amendments. The results of cumulative CO₂–C emissions, relative priming effects, and carbon storage indicate that BC reduces C‐mineralization, resulting in greater C‐sequestration compared with other BW amendments, and the magnitude of this effect initially increases and then decreases and stabilizes over time, possibly due to the presence of recalcitrant‐C (4.92 mg‐C g^?1‐soil) in BC, the reduced microbial activity, and the sorption of labile organic carbon (OC) onto BC particles.     

Reconstructing long‐term changes (150 years) in the carbon cycle of a clear‐water lake based on the stable carbon isotope composition (δ13C) of chironomid and cladoceran subfossil remains

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Crystal structure and luminescence properties of the blue‐green‐emitting Ba9(Lu,Y)2Si6O24:Ce3+ phosphor

Samples of the Ba₉(Lu_2‐xY_x)Si₆O₂₄:Ce³⁺ (x = 0–2) blue‐green phosphors were synthesized by solid‐state reactions. All the samples exhibited a rhombohedral crystal structure. As the Y³⁺ concentration increased, the diffraction peaks shifted to the small angle region and the lattice parameters increased due to the larger ionic radius of Y³⁺ (r = 0.900 Å) compared with that of Lu³⁺ (r = 0.861 Å). Under 400 nm excitation, samples exhibited strong blue‐green emissions around 490 nm. The emission bands had a slight blue shift that resulted from weak crystal‐field splitting with increasing Y³⁺ concentration. Luminescence intensity and quantum efficiency (QE) decreased with increasing Y³⁺ concentration. The internal QE decreased from 74 to 50% and the external QE decreased from 50 to 34% as x increased from 0 to 2. The thermal stability of the Lu series was better than that of the Y‐series. The excitation band peak around 400 nm matched well with the emission light from the efficient near‐ultraviolet (NUV) chip. These results indicate promising applications for these NUV‐based white light‐emitting diodes.     

Biosilica‐loaded poly(ϵ‐caprolactone) nanofibers mats provide a morphogenetically active surface scaffold for the growth and mineralization of the osteoclast‐related SaOS‐2 cells

Bioprinting/3D cell printing procedures for the preparation of scaffolds/implants have the potential to revolutionize regenerative medicine. Besides biocompatibility and biodegradability, the hardness of the scaffold material is of critical importance to allow sufficient mechanical protection and, to the same extent, allow migration, cell–cell, and cell–substrate contact formation of the matrix‐embedded cells. In the present study, we present a strategy to encase a bioprinted, cell‐containing, and soft scaffold with an electrospun mat. The electrospun poly(?‐caprolactone) (PCL) nanofibers mats, containing tetraethyl orthosilicate (TEOS), were subsequently incubated with silicatein. Silicatein synthesizes polymeric biosilica by polycondensation of ortho‐silicate that is formed from prehydrolyzed TEOS. Biosilica provides a morphogenetically active matrix for the growth and mineralization of osteoblast‐related SaOS‐2 cells in vitro. Analysis of the microstructure of the 300–700 nm thick PCL/TEOS nanofibers, incubated with silicatein and prehydrolyzed TEOS, displayed biosilica deposits on the mats formed by the nanofibers. We conclude and propose that electrospun PCL nanofibers mats, coated with biosilica, may represent a morphogenetically active and protective cover for bioprinted cell/tissue‐like units with a suitable mechanical stability, even if the cells are embedded in a softer matrix.     

Characterization of a type of β‐bend ribbon spiral generated by the repeating (Xaa–Yaa–Aib–Pro) motif: The solution structure of harzianin HC IX,a 14‐residue peptaibol forming voltage‐dependent ion channels

The three‐dimensional solution structure of harzianin HC IX, a peptaibol antibiotic isolated from the fungus Trichoderma harzianum, was determined using CD, homonuclear, and heteronuclear two‐dimensional nmr spectroscopy combined with molecular modeling. This 14‐residue peptide, Ac Aib¹ Asn² Leu³ Aib⁴ Pro⁵ Ala⁶ Ile⁷ Aib⁸ Pro⁹ Iva¹⁰ Leu¹¹ Aib¹² Pro¹³ Leuol¹⁴ (Aib, α‐aminoisobutyric acid; Iva, isovaline; Leuol, leucinol), is a main representative of a short‐sequence peptaibol class characterized by an acetylated N‐terminus, a C‐terminal amino alcohol, and the presence of three Aib‐L ‐Pro motifs at positions 4–5, 8–9, and 12–13, separated by two dipeptide units. In spite of a lower number of residues, compared to the 18/20‐residue peptaibols such as alamethicin, harzianin HC IX exhibits remarkable membrane‐perturbing properties. It interacts with phospholipid bilayers, increasing their permeability and forming voltage‐gated ion channels through a mechanism slightly differing from that proposed for alamethicin. Sequence‐specific ¹H‐ and ¹³C‐nmr assignments and conformational nmr parameters (³J_NHCαH coupling constants, quantitative nuclear Overhauser enhancement data, temperature coefficients of amide and carbonyl groups, NH–ND exchange rates) were obtained in methanol solution. Sixty structures were calculated based on 98 interproton distance restraints and 6 Φ dihedral angle restraints, using high temperature restrained molecular dynamics and energy minimization. Thirty‐seven out of the sixty generated structures were consistent with the nmr data and were convergent. The peptide backbone consists in a ribbon of overlapping β‐turns twisted into a continuous spiral from Asn² to Leuol¹⁴ and forming a 26 Å long helix‐like structure. This structure is slightly amphipathic, with the three Aib–Pro motifs aligned on the less hydrophobic face of the spiral where the Asn² side chain is also present, while the more hydrophobic bulky side chains of leucines, isoleucine, isovaline, and leucinol are located on the concave side. The repetitive (Xaa–Yaa–Aib–Pro) tetrapeptide subunit, making up the peptide sequence, is characterized by four sets of (Φ,Ψ) torsional angles, with the following mean values: Φ_i = −90°, Ψ_i = −27°; Φ_i+1 = −98°, Ψ_i+1 = −17°; Φ_i+2 = −49°, Ψ_i+2 = −50°; Φ_i+3 = −78°, Ψ_i+3 = +3°. We term this particular structure, specifically occurring in the case of (Xaa–Yaa–Aib–Pro)_n sequences, the (Xaa–Yaa–Aib–Pro)‐β‐bend ribbon spiral. It is stabilized by 4 → 1 intramolecular hydrogen bonds and differs from both the canonical 3₁₀‐helix made of a succession of type III β‐turns and from the β‐bend ribbon spiral that has been described in the case of (Aib–Pro)n peptide segments. © 1999 John Wiley & Sons, Inc. Biopoly 50: 71–85, 1999     

Docking and molecular dynamics simulations of the Fyn‐SH3 domain with free and phospholipid bilayer‐associated 18.5‐kDa myelin basic protein (MBP)—Insights into a noncanonical and fuzzy interaction

The molecular details of the association between the human Fyn‐SH3 domain, and the fragment of 18.5‐kDa myelin basic protein (MBP) spanning residues S38–S107 (denoted as xα2‐peptide, murine sequence numbering), were studied in silico via docking and molecular dynamics over 50‐ns trajectories. The results show that interaction between the two proteins is energetically favorable and heavily dependent on the MBP proline‐rich region (P93‐P98) in both aqueous and membrane environments. In aqueous conditions, the xα2‐peptide/Fyn‐SH3 complex adopts a “sandwich”"‐like structure. In the membrane context, the xα2‐peptide interacts with the Fyn‐SH3 domain via the proline‐rich region and the β‐sheets of Fyn‐SH3, with the latter wrapping around the proline‐rich region in a form of a clip. Moreover, the simulations corroborate prior experimental evidence of the importance of upstream segments beyond the canonical SH3‐ligand. This study thus provides a more‐detailed glimpse into the context‐dependent interaction dynamics and importance of the β‐sheets in Fyn‐SH3 and proline‐rich region of MBP. Proteins 2017; 85:1336–1350. © 2017 Wiley Periodicals, Inc.     

The Inhibitor of wax 1 locus (Iw1) prevents formation of β‐ and OH‐β‐diketones in wheat cuticular waxes and maps to a sub‐cM interval on chromosome arm 2BS

Glaucousness is described as the scattering effect of visible light from wax deposited on the cuticle of plant aerial organs. In wheat, two dominant genes lead to non‐glaucous phenotypes: Inhibitor of wax 1 (Iw1) and Iw2. The molecular mechanisms and the exact extent (beyond visual assessment) by which these genes affect the composition and quantity of cuticular wax is unclear. To describe the Iw1 locus we used a genetic approach with detailed biochemical characterization of wax compounds. Using synteny and a large number of F₂ gametes, Iw1 was fine‐mapped to a sub‐cM genetic interval on wheat chromosome arm 2BS, which includes a single collinear gene from the corresponding Brachypodium and rice physical maps. The major components of flag leaf and peduncle cuticular waxes included primary alcohols, β‐diketones and n‐alkanes. Small amounts of C19–C27 alkyl and methylalkylresorcinols that have not previously been described in wheat waxes were identified. Using six pairs of BC₂F₃ near‐isogenic lines, we show that Iw1 inhibits the formation of β‐ and hydroxy‐β‐diketones in the peduncle and flag leaf blade cuticles. This inhibitory effect is independent of genetic background or tissue, and is accompanied by minor but consistent increases in n‐alkanes and C₂₄ primary alcohols. No differences were found in cuticle thickness and carbon isotope discrimination in near‐isogenic lines differing at Iw1.     

Identification of the role of bone morphogenetic protein (BMP) and transforming growth factor‐β (TGF‐β) signaling in the trajectory of serotonergic differentiation in a rapid assay in mouse embryonic stem cells in vitro

The mechanism by which extracellular molecules control serotonergic cell fate remains elusive. Recently, we showed that noggin, which inactivates bone morphogenetic proteins (BMPs), induces serotonergic differentiation of mouse embryonic (ES) and induced pluripotent stem cells with coordinated gene expression along the serotonergic lineage. Here, we created a rapid assay for serotonergic induction by generating knock‐in ES cells expressing a naturally secreted Gaussia luciferase driven by the enhancer of Pet‐1/Fev, a landmark of serotonergic differentiation. Using these cells, we performed candidate‐based screening and identified BMP type I receptor kinase inhibitors LDN‐193189 and DMH1 as activators of luciferase. LDN‐193189 induced ES cells to express the genes encoding Pet‐1, tryptophan hydroxylase 2, and the serotonin transporter, and increased serotonin release without altering dopamine release. In contrast, TGF‐β receptor inhibitor SB‐431542 selectively inhibited serotonergic differentiation, without changing overall neuronal differentiation. LDN‐193189 inhibited expression of the BMP signaling target gene Id, and induced the TGF‐β target gene Lefty, whereas the opposite effect was observed with SB‐431542. This study thus provides a new tool to investigate serotonergic differentiation and suggests that inhibition of BMP type I receptors and concomitant activation of TGF‐β receptor signaling are implicated in serotonergic differentiation.