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Yamamoto, M.

Publications and source records attributed to Yamamoto, M..

At least 55 records · Page 3Linked to original sources

Self-incompatibility phenotypes of SRK mutants can be predicted with high accuracy

Only very limited information is available on why some non-synonymous variants severely alter gene function while others have no effect. To identify the characteristic features of mutations that strongly influence gene function, this study focused on S-locus receptor kinase, SRK, which encodes a highly polymorphic receptor kinase expressed in stigma papillary cells that underlies a female determinant of self-incompatibility in Brassicaceae. A set of 299 Arabidopsis thaliana transformants expressing mutated SRKb from A. lyrata was constructed and analyzed to determine the genotype and self-incompatibility phenotype of each transformant. Almost all the transformants showing the self-incompatibility defect contained mutations in AlSRKb that altered localization to the plasma membrane. The observed mutations occurred in amino acid residues that were highly conserved across S haplotypes and whose predicted locations were in the interior of the protein. These mutations were likely to underlie the self-incompatibility defect as they caused significant changes to amino acid properties. Such findings suggested that mutations causing the self-incompatibility defect were more likely to result from changes to AlSRKb biosynthesis than from loss of function. In addition, this study showed the RandomForest and Extreme Gradient Boosting methods could predict self-incompatibility phenotypes of SRK mutants with high accuracy.

plant biology↗

Next-generation sequencing analysis with a population-specific reference genome

Next-generation sequencing (NGS) has become widely available and is routinely used in basic research and clinical practice. The reference genome sequence is an essential resource for NGS analysis, and several population-specific reference genomes have recently been constructed to provide a choice to deal with the vast genetic diversity of human samples. However, resources supporting population-specific references are insufficient, and it is burdensome to perform analysis using these reference genomes. Here, we constructed a set of resources to support NGS analysis using the Japanese reference genome sequence, JG. We created resources for variant calling, gene and repeat element annotations, variant-effect prediction, read mappability, and RNA-seq analysis. We also provide a resource for reference coordinate conversion for further annotation enrichment. We then provide a variant calling protocol using JG-based resources. Our resources provide a guide to prepare sufficient resources for the use of population-specific reference genomes and can facilitate the migration of reference genomes.

bioinformatics↗

Erythropoietin production in embryonic neural cells is controlled by hypoxia-inducible factors and histone deacetylases in an undifferentiated state

During mammalian development, production sites of the erythroid growth factor erythropoietin (EPO) shift from the neural tissues to the liver in embryos and to the adult kidneys. Embryonic neural EPO-producing (NEP) cells, a subpopulation of neuroepithelial and neural crest cells, express the Epo gene between embryonic day (E) 8.5 and E11.5 to promote primitive erythropoiesis in mice. While Epo gene expression in the liver and kidney is induced under hypoxic conditions through hypoxia-inducible transcription factor (HIF) 2, the Epo gene regulatory mechanisms in NEP cells remain to be elucidated. This study confirms the presence of cells coexpressing the genes encoding EPO and HIF2 in E9.5 neural tubes, where the hypoxic microenvironment activates HIF1. In human neural progenitors and mouse embryonic neural tissues, a HIF-activating compound upregulated EPO expression, and this induction was blocked by inhibiting HIFs. Additionally, a cell line of NEP cell derivatives that no longer expressed the Epo gene demonstrated that histone deacetylase inhibitors (HDACIs) reactivate EPO production while rejuvenating the cells. HDACIs also induced EPO gene expression in SK-N-BE(2)c human neuroblastoma cells and mouse primary neural crest cells. Thus, EPO production is controlled by epigenetic mechanisms and hypoxia signaling in an immature state of hypoxic NEP cells.

molecular biology↗

In vivo CRISPR screens identify novel virulence genes among proteins of unassigned subcellular localization in Toxoplasma

The research field to identify and characterize virulence genes in Toxoplasma gondii has been dramatically advanced by a series of in vivo CRISPR screens. Although subcellular localizations of thousands of proteins were predicted by the spatial proteomic method called hyperLOPIT, those of more than 1000 proteins remained unassigned and their essentiality in virulence was also unknown. In this study, we generated two small-scale gRNA libraries targeting approximately 600 hyperLOPIT-unassigned proteins and performed in vivo CRISPR screens. As a result, we identified several in vivo fitness-conferring genes that were previously unreported. We further characterized two candidates, TgGTPase and TgRimM, which are localized in the cytoplasm and the apicoplast, respectively. Both genes are essential for parasite virulence and widely conserved in the phylum Apicomplexa. Collectively, our current study provides a resource for estimating the in vivo essentiality of Toxoplasma proteins with previously unknown localizations. IMPORTANCEToxoplasma gondii is a protozoan parasite that causes severe infection in immunocompromised patients or newborns. Toxoplasma possesses more than 8000 genes; however, the genes that determine parasite virulence were not fully identified. The apicomplexan parasites, including Toxoplasma, developed unique organelles that do not exist in other model organisms; thus, determining the subcellular location of parasite proteins is important for understanding their functions. Here, we used in vivo CRISPR genetic screens that enabled us to investigate hundreds of genes in Toxoplasma during mouse infection. We screened approximately 600 parasite proteins with previously unknown subcellular localizations. We identified many novel genes that confer parasite fitness in mice. Among the top hits, we characterized two essential virulence genes, TgGTPase and TgRimM, which are widely conserved in the phylum Apicomplexa. Our findings will contribute to understanding how apicomplexans adapt to the host environment and cause disease.

microbiology↗

Cost-Effective Approaches to Elucidate Intergeneric Relationships of Plants: Utilizing Multiple Conserved Nuclear Genes and Whole Chloroplast Genomes

The chloroplast (cp) genome is a widely used tool for exploring plant evolutionary relationships, yet its effectiveness in fully resolving these relationships remains uncertain. Integrating cp genome data with nuclear DNA information offers a more comprehensive view but often requires separate datasets. In response, we employed the same raw read sequencing data to construct cp genome-based trees and nuclear DNA phylogenetic trees using Read2Tree, a cost-efficient method for extracting conserved nuclear gene sequences from raw read data, focusing on the Aurantioideae subfamily, which includes Citrus and its relatives. The resulting nuclear DNA trees were consistent with existing nuclear evolutionary relationships derived from high-throughput sequencing, but diverged from cp genome-based trees. To elucidate the underlying complex evolutionary processes causing these discordances, we implemented an integrative workflow that utilized multiple alignments of each gene generated by Read2Tree, in conjunction with other phylogenomic methods. Our analysis revealed that incomplete lineage sorting predominantly drives these discordances, while introgression and ancient introgression also contribute to topological discrepancies within certain clades. This study underscores the cost-effectiveness of using the same raw sequencing data for both cp and nuclear DNA analyses in understanding plant evolutionary relationships.

genomics↗

A potential pathway that links intron retention with the physiological recovery by a Japanese herbal medicine

Our previous experiments with klotho mice (i.e., klotho knockout mice) showed that aberrant intron retention (IR) occurs in a pre-symptomatic state of aging and can be restored to the normal state by administration of Juzentaihoto (JTT), a formula of the Japanese herbal medicine (referred to as kampo; Okada et al., 2021). To explain that this phenomenon is not just a specific example observed in klotho mice, but is due to a universal cause that may be common in a pre-symptomatic state, we re-analyzed the data for genes that were differentially expressed in the klotho liver in response to JTT. Our data showed that AMPK signaling was activated in these mice, resulting in inhibition of anabolic pathways including protein synthesis and activation of catabolic pathways including lipolysis in various organs. These data were consistent with the observation that klotho mice appeared to be in a perpetual state of pseudo-starvation, i.e., based on their overall metabolic profile. The abnormally increased incidence of IR (IncIR) in the liver of klotho mice could be classified into three types according to their transcriptional status, revealing that each of all the three types of IncIR was caused by AMPK activation, a consequence of the pseudo-starvation state exhibited by these mice. Furthermore, we showed that both the transcriptional drift variance and the IR drift variance can be useful for visually assessing recovery from the pseudo-starvation state of klotho mice after administration of JTT. With these data, we propose a novel pathway linking intron retention to changes in the physiological state such as starvation, resulting in the maintenance of cellular homeostasis.

bioinformatics↗

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a Partial STING Agonist, Competes for Human STING Activation

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA can not fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative--3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xhanthen-9one (HHMX)--that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.

immunology↗

DeepLabCut-based Behavioural and Posture Analysis in a Cricket

Circadian rhythms are indispensable intrinsic programs that regulate the daily rhythmicity of physiological processes, such as feeding and sleep. The cricket has been employed as a model organism for understanding the neural mechanisms underlying circadian rhythms in insects. However, previous studies measuring rhythm-controlled behaviours only analysed locomotive activity using seesaw-type and infrared sensor-based actometers. Meanwhile, advances in deep learning techniques have made it possible to analyse animal behaviour and posture using software that is devoid of human bias and does not require physical tagging of individual animals. Here, we present a system that can simultaneously quantify multiple behaviours in individual crickets, such as locomotor activity, feeding, and sleep-like states, in the long-term, using DeepLabCut, a supervised machine learning-based software for body keypoints labeling. Our system successfully labelled the six body parts of a single cricket with a high level of confidence and produced reliable data showing the diurnal rhythms of multiple behaviours. Our system also enabled the estimation of sleep-like states by focusing on posture, instead of immobility time, which is a conventional parameter. We anticipate that this system will provide an opportunity for simultaneous and automatic prediction of cricket behaviour and posture, facilitating the study of circadian rhythms.

animal behavior and cognition↗

A fine-scale genetic map of the Japanese population

Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium--a non-random association of alleles among loci--by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10,092,573 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals. These individuals genotypes were determined by high-coverage (30x) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents and offsprings genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the HapMap worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.

genetics↗

Genomic surveillance of antimicrobial-resistant Escherichia coli in fecal sludge and sewage in Uganda

The global increase of antimicrobial resistance (AMR) is a major public health concern. An effective AMR surveillance tool is needed to track the emergence and spread of AMR. Wastewater surveillance has been proposed as a resource-efficient tool for monitoring AMR carriage in the community. Here, we performed genomic surveillance of antimicrobial-resistant Escherichia coli obtained from fecal sludge and sewage in Uganda to gain insights into E. coli epidemiology and AMR burden in the underlying population. Selective media containing different antibiotic combinations (cefotaxime, ciprofloxacin, cefotaxime + ciprofloxacin + gentamicin) were used to obtain antimicrobial-resistant E. coli from fecal sludge and sewage. Short-read sequencing was performed for the obtained isolates, and a subset of isolates (selected from predominant sequence types (STs)) was also subjected to long-read sequencing. Genomic analysis of the obtained E. coli isolates (n = 181) revealed the prevalence of clonal complex 10, including ST167 (n = 43), ST10 (n = 28), ST1284 (n = 17), and ST617 (n = 4), in both fecal sludge and sewage, irrespective of antibiotics used for selection. We also detected global high-risk clones ST1193 (n = 10) and ST131 (n = 2 clade A, n = 3 subclade C1-M27, and n = 1 subclade C2). Diverse AMR determinants, including extended-spectrum {beta}-lactamase genes (mostly blaCTX-M-15) and mutations in gyrA and parC, were identified. Analysis of the completed genomes revealed that diverse IncF plasmids and chromosomal integration were the major contributors to the spread of AMR genes in the predominant STs. This study showed that a combination of sewage surveillance (or fecal sludge surveillance) and whole-genome sequencing can be a powerful tool for monitoring AMR carriage in the underlying population.

microbiology↗

Anti-nucleolin aptamer, iSN04, inhibits the inflammatory responses in myoblasts by modulating the β-catenin/NF-κB signaling pathway

A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to be a nucleic acid drug for the muscle wasting associated with chronic diseases. The present study investigated the anti-inflammatory mechanism of iSN04 in the murine myoblast cell line C2C12. Tumor necrosis factor- (TNF-) or Toll-like receptor (TLR) ligands (Pam3CSK4 and FSL-1) induced nuclear translocation and transcriptional activity of nuclear factor-{kappa}B (NF-{kappa}B), resulting in upregulated expression of TNF- and interleukin-6. Pre-treatment with iSN04 significantly suppressed these inflammatory responses by inhibiting the nuclear accumulation of {beta}-catenin induced by TNF- or TLR ligands. These results demonstrate that antagonizing nucleolin with iSN04 downregulates the inflammatory effect mediated by the {beta}-catenin/NF-{kappa}B signaling pathway in myoblasts. In addition, the anti-inflammatory effects of iSN04 were also observed in smooth muscle cells and pre-adipocytes, suggesting that iSN04 may be useful in preventing inflammation induced by metabolic disorders.

cell biology↗

Context-Dependent Modification of PFKFB3 in Hematopoietic Stem Cells Promotes Anaerobic Glycolysis and Ensures Stress Hematopoiesis

Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of adenosine triphosphate (ATP) levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells. Key PointsO_LICombined isotope tracing, mathematical modeling, and single cell ATP analysis enable high-resolution evaluation of blood cell metabolism. C_LIO_LIUnder stress, HSCs quickly accelerate glycolysis to meet ATP demands and maintain hematopoiesis via context-dependent PFKFB3 activation. C_LI

cell biology↗

The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling

Various gut bacteria, including Lactobacillus plantarum, possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo-cis-6,trans-11-octadecadienoic acid ({gamma}KetoC), a {gamma}-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with {gamma}KetoC significantly suppressed proliferation of CD4+ T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c+ cells isolated from the spleen. {gamma}KetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of {gamma}KetoC on DCs. We also found that {gamma}KetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of {gamma}KetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2-/- BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of {gamma}KetoC in a dextran sodium sulfate-induced colitis model. The oral administration of {gamma}KetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2+/- mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2-/- mice even with the administration of {gamma}KetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in {gamma}KetoC-mediated anti-inflammatory responses.

immunology↗

Horizontal transmission of penicillin binding protein 1A caused a nationwide spread of β-lactam resistance in pneumococci

The emergence and spread of drug-resistant bacteria continue to be a global crisis. The mechanism of the resistance spread via mobile genetic elements such as plasmids is well known, however, the impact of the natural transformation on the spread remains unclear. Streptococcus pneumoniae is well known to be a transformable pathogen by natural competence and they become {beta}-lactam resistance by the acquisition of chromosomal genetic elements including mutated PBPs by natural transformation. To trace the transmission of pneumococcal PBPs among nationwide pediatric population and analyze the impact of transformed PBPs to {beta}-lactam resistance, we collected and analyzed more than 1300 isolates of S. pneumoniae through nationwide surveillance study for pediatric pneumococcal diseases between 2012-2017 in Japan. We discovered a high prevalence of a specific PBP1A type (pbp1a-13) in {beta}-lactam resistant pneumococci that had a 370SSMK substitution in their {beta}-lactam binding SXXK motif, suggesting that this pbp1a-13 transferred horizontally between different clones resulting in emergence and spread of {beta}-lactam resistant pneumococcal clones. Divergence dating analysis suggested that pbp1a-13 was inserted into major resistant lineages in the early 1990s through the 2000s, before introduction of pneumococcal conjugate vaccines in Japan. Our additional analysis for pneumococcal isolates that were recovered in the 90s in Japan suggested that pbp1a-13 in GPSC1 (serotype 19F-CC236) and GPSC14 (serotype 23F-CC242) isolates were the origin of the currently spread pbp1a-13. We provide evidence of pbp1a horizontal transmission at a nationwide scale and highlight the importance of PBP profile monitoring for identifying the emergence and spread of resistant pneumococci lineages.

microbiology↗

Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I.

Upon infection with Toxoplasma gondii, host cells produce immune-related GTPases (IRGs) to kill the parasite. T. gondii counters this response by releasing ROP18 kinase, which inactivates IRG GTPases and inhibits their recruitment to the T. gondii parasitophorous vacuole (PV). However, the molecular mechanisms of this process are entirely unknown. Here we report the atomic structures of Irgb6 with a phosphomimetic mutation by ROP18. The mutant has lower GTPase activity and is not recruited to the PV membrane (PVM). The crystal structure shows the mutant exhibit a distinct conformation from the physiological nucleotide-free form, thus preventing GTPase cycling. This change allosterically modifies the conformation of the membrane-binding interface, preventing physiological PVM-binding. Docking simulation of PI5P also supports the impaired binding of the mutant to PVM. We thus demonstrate the structural basis for T. gondii escape from host cell-autonomous defense, and provide a structural model for regulating enzymatic activity by phosphorylation.

microbiology↗

PNPO-PLP Axis Senses Prolonged Hypoxia by Regulating Lysosomal Activity

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen sensing systems inducing acute hypoxic response, including HIF pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here, we show that pyridoxine 5-phosphate oxidase (PNPO) that catalyzes bioactivation of vitamin B6 serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decline of PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5-phosphate (PLP), and inhibited lysosomal activity, leading to the augmentation of inflammatory response of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing, which gradually turns down and up the PLP-dependent metabolism according to prolonged changes in oxygen availability.

biochemistry↗

Elucidating polymorphs of crystal structures with intensity-based hierarchical clustering analysis on multiple diffraction datasets

In macromolecular structure determination using X-ray diffraction from multiple crystals, the presence of different structures (structural polymorphs) necessitates the classification of diffraction data for appropriate structural analysis. Hierarchical clustering analysis (HCA) is a promising technique that has so far been used to extract isomorphous data, mainly for single structure determination. Although in principle the use of HCA can be extended to detect polymorphs, the absence of a reference for defining a threshold used for grouping the isomorphous datasets ( isomorphic threshold) poses a challenge. Here, we have applied unit cell-based and intensity-based HCAs to the datasets of apo-trypsin and inhibitor-bound trypsin that were mixed post-data acquisition to investigate how effective HCA is in classifying polymorphous datasets. Single-step intensity-based HCA successfully classified polymorphs with a certain isomorphic threshold. In datasets of several samples containing an unknown degree of structural heterogeneity, polymorphs could be identified by intensity-based HCA using the suggested isomorphic threshold. Polymorphs were also detected in single crystals using the data collected by the continuous helical scheme. These findings are expected to facilitate the determination of multiple structural snapshots by exploiting automated data collection and analysis. SynopsisSingle-step intensity-based hierarchical clustering is demonstrated to allow the detection of structural polymorphs in the diffraction datasets obtained from multiple crystals. By splitting the datasets collected by continuous helical scheme into several chunks, both inter and intra-crystal polymorphs can be successfully analyzed.

molecular biology↗

Hedgehog Activity Gradient in Combination with Transcription Network Confers Multiple Hypothalamic Identities

During development, the hypothalamus emerges from the ventral diencephalon of the neural tube and is regionalised into several distinct functional domains. Each domain is characterised by different combinations of transcription factors, the expression of which is regulated by signalling molecules and downstream transcriptional networks. Transcription factors, including Nkx2.1, Nkx2.2, Pax6 and Rx, are expressed in the presumptive hypothalamus and its surrounding regions from an early developmental stage and play critical roles in the development of these areas. However, the regulation of transcription factor expression and the details of the transcriptional network among them have not been fully elucidated. As early hypothalamus development takes place in the ventral region of the forebrain where Sonic Hedgehog (Shh) is expressed, we focused on the relationship between Shh and its downstream transcription factors and investigated the transcriptional regulation along the dorsal-ventral axis. Using a reporter mouse line, in vitro neural differentiation of mouse embryonic stem cells and gene overexpression in chick embryos, we found that Pax6, Nkx2.1 and Nkx2.2 are regulated epistatically by different Shh signal intensities. Nkx2.1 and Nkx2.2 mutually repress each other; however, they induce each other in a non-cell-autonomous manner. Moreover, Rx resides upstream of all these transcription factors and determines the location of the hypothalamic region along the dorsal-ventral and anterior-posterior regulations. Finally, we found that the Shh signal demarcates the diencephalic region from the retinal area. Our findings suggest that Shh signalling, and its downstream transcription network, are required for hypothalamic regionalisation and establishment of diencephalic cell fate.

developmental biology↗