RESUMO
The meninges are critical for the brain functions, but the diversity of meningeal cell types and intercellular interactions have yet to be thoroughly examined. Here we identify a population of meningeal lymphatic supporting cells (mLSCs) in the zebrafish leptomeninges, which are specifically labeled by ependymin. Morphologically, mLSCs form membranous structures that enwrap the majority of leptomeningeal blood vessels and all the mural lymphatic endothelial cells (muLECs). Based on its unique cellular morphologies and transcriptional profile, mLSC is characterized as a unique cell type different from all the currently known meningeal cell types. Because of the formation of supportive structures and production of pro-lymphangiogenic factors, mLSCs not only promote muLEC development and maintain the dispersed distributions of muLECs in the leptomeninges, but also are required for muLEC regeneration after ablation. This study characterizes a newly identified cell type in leptomeninges, mLSC, which is required for muLEC development, maintenance, and regeneration.
Assuntos
Células Endoteliais , Meninges , Peixe-Zebra , Animais , Meninges/citologia , Meninges/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/citologia , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Vasos Linfáticos/citologia , Vasos Linfáticos/metabolismo , Animais Geneticamente Modificados , Linfangiogênese/fisiologia , Regeneração/fisiologiaRESUMO
During vascular development, radial glial cells (RGCs) regulate vascular patterning in the trunk and contribute to the early differentiation of the blood-brain barrier. Ablation of RGCs results in excessive sprouting vessels or the absence of bilateral vertebral arteries. However, interactions of RGCs with later brain vascular networks after pattern formation remain unknown. Here, we generated a her4.3 transgenic line to label RGCs and applied the metronidazole/nitroreductase system to ablate her4.3+ RGCs. The ablation of her4.3+ RGCs led to the collapse of the cerebral vascular network, disruption of the blood-brain barrier, and downregulation of Wnt signaling. The inhibition of Wnt signaling resulted in the collapse of cerebral vasculature, similar to that caused by her4.3+ RGC ablation. The defects in the maintenance of brain vasculature resulting from the absence of her4.3+ RGCs were partially rescued by the activation of Wnt signaling or overexpression of Wnt7aa or Wnt7bb. Together, our study suggests that her4.3+ RGCs maintain the cerebral vascular network through Wnt signaling.
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In zebrafish, brain lymphatic endothelial cells (BLECs) are essential for meningeal angiogenesis and cerebrovascular regeneration. Although epidermal growth factor-like domain 7 (Egfl7) has been reported to act as a pro-angiogenic factor, its roles in lymphangiogenesis remain unclear. Here, we show that Egfl7 is expressed in both blood and lymphatic endothelial cells. We generate an egfl7 cq180 mutant with a 13-bp-deletion in exon 3 leading to reduced expression of Egfl7. The egfl7 cq180 mutant zebrafish exhibit defective formation of BLEC bilateral loop-like structures, although trunk and facial lymphatic development remains unaffected. Moreover, while the egfl7 cq180 mutant displays normal BLEC lineage specification, the migration and proliferation of these cells are impaired. Additionally, we identify integrin αvß3 as the receptor for Egfl7. αvß3 is expressed in the CVP and sprouting BLECs, and blocking this integrin inhibits the formation of BLEC bilateral loop-like structures. Thus, this study identifies a role for Egfl7 in BLEC development that is mediated through the integrin αvß3.
Assuntos
Encéfalo , Células Endoteliais , Integrina alfaVbeta3 , Linfangiogênese , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Humanos , Animais Geneticamente Modificados , Encéfalo/metabolismo , Movimento Celular/genética , Proliferação de Células , Família de Proteínas EGF/metabolismo , Família de Proteínas EGF/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/genética , Linfangiogênese/genética , Mutação , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genéticaRESUMO
Coat protein complex I (COPI) vesicles mediate the retrograde transfer of cargo between Golgi cisternae and from the Golgi to the endoplasmic reticulum (ER). However, their roles in the cell cycle and proliferation are unclear. This study shows that TANGO6 associates with COPI vesicles via two transmembrane domains. The TANGO6 N- and C-terminal cytoplasmic fragments capture RNA polymerase II subunit B (RPB) 2 in the cis-Golgi during the G1 phase. COPI-docked TANGO6 carries RPB2 to the ER and then to the nucleus. Functional disruption of TANGO6 hinders the nuclear entry of RPB2, which accumulates in the cytoplasm, causing cell cycle arrest in the G1 phase. The conditional depletion or overexpression of TANGO6 in mouse hematopoietic stem cells results in compromised or expanded hematopoiesis. Our study results demonstrate that COPI vesicle-associated TANGO6 plays a role in the regulation of cell cycle progression by directing the nuclear transfer of RPB2, making it a potential target for promoting or arresting cell expansion.
Assuntos
Complexo I de Proteína do Envoltório , Retículo Endoplasmático , Complexo de Golgi , RNA Polimerase II , Animais , Camundongos , Transporte Ativo do Núcleo Celular , Proliferação de Células , Complexo I de Proteína do Envoltório/genética , Complexo I de Proteína do Envoltório/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , RNA Polimerase II/metabolismoRESUMO
During embryonic development, the inductive molecules produced by local origins normally arrive at their target tissues in a nondirectional, diffusion manner. The target organ precursor cells must correctly interpret these inductive signals to ensure proper specification/differentiation, which is dependent on two prerequisites: (i) obtaining cell-intrinsic competence; and (ii) receiving correct inductive signals while resisting incorrect ones. Gain of intrinsic competence could avoid a large number of misinductions because the incompetent cells are nonresponsive to inductive signals. However, in cases of different precursor cells with similar competence and located in close proximity, resistance to incorrect inductive signals is essential for accurate determination of cell fate. Here we outline the mechanisms of how organ precursors respond to correct and incorrect inductive signals.
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Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.
Assuntos
Hepatopatias , Fator A de Crescimento do Endotélio Vascular , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases , Regeneração Hepática/fisiologia , Hepatócitos , Proliferação de Células , Alvo Mecanístico do Complexo 1 de Rapamicina , Fígado , MamíferosRESUMO
A major cause of intestinal failure (IF) is intestinal epithelium necrosis and massive loss of enterocytes, especially in the jejunum, the major intestinal segment in charge of nutrient absorption. However, mechanisms underlying jejunal epithelial regeneration after extensive loss of enterocytes remain elusive. Here, we apply a genetic ablation system to induce extensive damage to jejunal enterocytes in zebrafish, mimicking the jejunal epithelium necrosis that causes IF. In response to injury, proliferation and filopodia/lamellipodia drive anterior migration of the ileal enterocytes into the injured jejunum. The migrated fabp6+ ileal enterocytes transdifferentiate into fabp2+ jejunal enterocytes to fulfill the regeneration, consisting of dedifferentiation to precursor status followed by redifferentiation. The dedifferentiation is activated by the IL1ß-NFκB axis, whose agonist promotes regeneration. Extensive jejunal epithelial damage is repaired by the migration and transdifferentiation of ileal enterocytes, revealing an intersegmental migration mechanism of intestinal regeneration and providing potential therapeutic targets for IF caused by jejunal epithelium necrosis.
Assuntos
Enterócitos , Jejuno , Animais , Peixe-Zebra , Transdiferenciação Celular , Mucosa Intestinal , NecroseRESUMO
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.
Assuntos
Cirrose Hepática Biliar , Animais , Cães , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Peixe-Zebra , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TORRESUMO
This study aims to understand the epidemiological characteristics of SARS-CoV-2 infection in the paediatric population during the outbreak of the Omicron variant in Shanghai. We retrospectively analysed the population-based epidemiological characteristics and clinical outcome of SARS-CoV-2 Omicron variant infection in children in Minhang District, Shanghai, based on the citywide surveillance system during the outbreak period in 2022 (March to May). During this time, a total of 63,969 cases of SARS-CoV-2 infection were notified in Minhang District, out of which 4,652 (7.3%) were children and adolescents <18 years. The incidence rate of SARS-CoV-2 infections in children was 153 per 10,000. Of all paediatric cases, 50% reported to be clinically symptomatic within 1-3 days after PCR confirmation by parents or themselves, with 36.3% and 18.9% of paediatric cases reporting fever and cough. Also, 58.4% of paediatric cases had received at least one dose of the COVID-19 vaccine and 52.1% had received two doses of the COVID-19 vaccination. Our findings are informative for the implementation of appropriate measures to protect children from the threat of SARS-CoV-2 infection.
Assuntos
COVID-19 , Adolescente , Criança , Humanos , China/epidemiologia , COVID-19/epidemiologia , Vacinas contra COVID-19 , Surtos de Doenças , Estudos Retrospectivos , SARS-CoV-2 , Masculino , Feminino , Recém-Nascido , Lactente , Pré-EscolarRESUMO
Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that both brg1 mRNA and protein were induced in cardiac endothelial cells after ventricular resection and endothelium-specific overexpression of dominant-negative Xenopus Brg1 (dn-xbrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that endothelium-specific overexpression of dn-xbrg1 changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulated notch gene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of the notch promoters in zebrafish.
RESUMO
When the proliferation of residual hepatocytes is prohibited, biliary epithelial cells (BECs) transdifferentiate into nascent hepatocytes to accomplish liver regeneration. Despite significant interest in transdifferentiation, little is known about the maintenance of nascent hepatocytes in post-injured environments. Here, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a mutant containing a nonsense mutation in the gene nibrin (nbn), which encodes a component of the Mre11-Rad50-Nbn (MRN) complex that activates DNA damage response (DDR). The regenerated hepatocytes cannot be maintained and exhibit apoptosis in the mutant. Mechanistically, the nbn mutation results in the abrogation of ATR-Chk1 signaling and accumulations of DNA damage in nascent hepatocytes, which eventually induces p53-mediated apoptosis. Furthermore, loss of rad50 or mre11a shows similar phenotypes. This study reveals that the activation of DDR by the MRN complex is essential for the survival of BEC-derived hepatocytes, addressing how to maintain nascent hepatocytes in the post-injured environments.
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Acquired digestive-respiratory tract fistulas occur with abnormal communication between the respiratory tract and digestive tract caused by a variety of benign or malignant diseases, leading to the alimentary canal contents in the respiratory tract. Although various departments have been actively exploring advanced fistula closure techniques, including surgical methods and multimodal therapy, some of which have gotten good clinical effects, there are few large-scale evidence-based medical data to guide clinical diagnosis and treatment. The guidelines update the etiology, classification, pathogenesis, diagnosis, and management of acquired digestive-respiratory tract fistulas. It has been proved that the implantation of the respiratory and digestive stent is the most important and best treatment for acquired digestive-respiratory tract fistulas. The guidelines conduct an in-depth review of the current evidence and introduce in detail the selection of stents, implantation methods, postoperative management and efficacy evaluation.
Assuntos
Fístula do Sistema Digestório , População do Leste Asiático , Fístula do Sistema Respiratório , Humanos , Consenso , Sistema Respiratório , Fístula do Sistema Respiratório/diagnóstico , Fístula do Sistema Respiratório/etiologia , Fístula do Sistema Respiratório/terapia , Stents/efeitos adversos , Resultado do Tratamento , Fístula do Sistema Digestório/diagnóstico , Fístula do Sistema Digestório/etiologia , Fístula do Sistema Digestório/terapiaRESUMO
Tooth germ injury can lead to abnormal tooth development and even tooth loss, affecting various aspects of the stomatognathic system including form, function, and appearance. However, the research about tooth germ injury model on cellular and molecule mechanism of tooth germ repair is still very limited. Therefore, it is of great importance for the prevention and treatment of tooth germ injury to study the important mechanism of tooth germ repair by a tooth germ injury model. Here, we constructed a Tg(dlx2b:Dendra2-NTR) transgenic line that labeled tooth germ specifically. Taking advantage of the NTR/Mtz system, the dlx2b+ tooth germ cells were depleted by Mtz effectively. The process of tooth germ repair was evaluated by antibody staining, in situ hybridization, EdU staining and alizarin red staining. The severely injured tooth germ was repaired in several days after Mtz treatment was stopped. In the early stage of tooth germ repair, the expression of phosphorylated 4E-BP1 was increased, indicating that mTORC1 is activated. Inhibition of mTORC1 signaling in vitro or knockdown of mTORC1 signaling in vivo could inhibit the repair of injured tooth germ. Normally, mouse incisors were repaired after damage, but inhibition/promotion of mTORC1 signaling inhibited/promoted this repair progress. Overall, we are the first to construct a stable and repeatable repair model of severe tooth germ injury, and our results reveal that mTORC1 signaling plays a crucial role during tooth germ repair, providing a potential target for clinical treatment of tooth germ injury.
Assuntos
Transdução de Sinais , Dente , Animais , Camundongos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/farmacologia , Dente/metabolismo , Germe de Dente/metabolismo , OdontogêneseRESUMO
Pancreatic ε-cells producing ghrelin are one type of endocrine cell found in islets, which have been shown to influence other intra-islet cells, especially in regulating the function of ß cells. However, the role of such cells during ß-cell regeneration is currently unknown. Here, using a zebrafish nitroreductase (NTR)-mediated ß-cell ablation model, we reveal that ghrelin-positive ε-cells in the pancreas act as contributors to neogenic ß-cells after extreme ß-cell loss. Further studies show that the overexpression of ghrelin or the expansion of ε-cells potentiates ß-cell regeneration. Lineage tracing confirms that a proportion of embryonic ε-cells can transdifferentiate to ß-cells, and that the deletion of Pax4 enhances this transdifferentiation of ε-cells to ß-cells. Mechanistically, Pax4 binds to the ghrelin regulatory region and represses its transcription. Thus, deletion of Pax4 derepresses ghrelin expression and causes producing more ghrelin-positive cells, enhancing the transdifferentiation of ε-cells to ß-cells and consequently potentiating ß-cell regeneration. Our findings reveal a previously unreported role for ε-cells during zebrafish ß-cell regeneration, indicating that Pax4 regulates ghrelin transcription and mediates the conversion of embryonic ε-cells to ß-cells after extreme ß-cell loss.
Assuntos
Fatores de Transcrição , Peixe-Zebra , Animais , Grelina/metabolismo , Proteínas de Homeodomínio/metabolismo , Pâncreas , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
In cases of end-stage liver diseases, the proliferation of existing hepatocytes is compromised, a feature of human chronic liver disease, in which most hepatocytes are dysfunctional. So far, liver transplantation represents the only curative therapeutic solution for advanced liver diseases, and the shortage of donor organs leads to high morbidity and mortality worldwide. The promising treatment is to prompt the biliary epithelial cells (BECs) transdifferentiation. However, the critical factors governing the initiation of BEC-derived liver regeneration are largely unknown. The zebrafish has advantages in large-scale genetic screens to identify the critical factors involved in liver regeneration. Here, we combined N-ethyl-N-nitrosourea screen, positional cloning, transgenic lines, antibody staining, and in situ hybridization methods and identified a liver regeneration defect mutant ( lrd ) using the zebrafish extensive liver injury model. Through positional cloning and genomic sequencing, we mapped the mutation site to rngtt . Loss of rngtt leads to the defects of BEC dedifferentiation, bipotential progenitor cell activation, and cell proliferation in the initiation stage of liver regeneration. The transdifferentiation from BECs to hepatocytes did not occur even at the late stage of liver regeneration. Mechanically, Rngtt transcriptionally regulates the attachment of mRNA cap to mTOR complex 1 (mTORC1) components and dnmt1 to maintain the activation of mTORC1 and DNA methylation in BECs after severe liver injury and prompt BEC to hepatocyte conversion. Furthermore, rptor and dnmt1 mutants displayed the same liver regeneration defects as rngtt mutation. In conclusion, our results suggest Rngtt is a new factor that initiates BEC-derived liver regeneration.
Assuntos
Regeneração Hepática , Peixe-Zebra , Animais , Humanos , DNA (Citosina-5-)-Metiltransferase 1 , Células Epiteliais , Hepatócitos/fisiologia , Fígado , Regeneração Hepática/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas de Peixe-Zebra/genéticaRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease caused by mutations in PKD1 and PKD2 that encode polycystin 1 (PC1) and polycystin 2 (PC2). PC1/2 localize to cilia of renal epithelial cells, and their function is believed to embody an inhibitory activity that suppresses the cilia-dependent cyst activation (CDCA) signal. Consequently, PC deficiency results in activation of CDCA and stimulates cyst growth. Recently, re-expression of PCs in established cysts has been shown to reverse PKD. Thus, the mode of action of PCs resembles a 'counterbalance in cruise control' to maintain lumen diameter within a designated range. Herein we review recent studies that point to novel arenas for future PC research with therapeutic potential for ADPKD.
Assuntos
Cistos , Doenças Renais Policísticas , Rim Policístico Autossômico Dominante , Humanos , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/complicações , Transdução de Sinais , Cistos/complicações , Rim/metabolismoRESUMO
Immunocytes, including the microglia, are crucial in the neurodegenerative process in old people. However, the understanding of regarding microglia heterogeneity and other involved immunocytes remains elusive. We analyzed 26,456 immunocytes from 12-and 26-month-old zebrafish brains at single-cell resolution. Microglia and T lymphocytes were detected in the brain at both time points. Two types of microglia were annotated, namely, ac+ microglia and xr+ microglia, which were clustered into subsets 1, 2, 3, 4, 5, and subsets 6, 7, 8, 9, respectively. Diversified microglia predominated the adult brains and cooperated with T cells to perform the functions of immune response and neuronal nutrition. We validated the specific microglia markers. The novel transgenic lines, Tg(lgals3bpb:eGFP) and Tg(apoc1:eGFP), were created, which faithfully labeled ac+ microglia and served as valuable labeling tools. However, the microglia population reduced while T cells of six subtypes intriguingly increased to serve as the primary immune cells in aged brains. Unlike in 12-month-old brains, T cells, together with microglia, exhibited a coordinated signature of inflammation in the 26-month-old brains. Our findings revealed the immunocytes atlas in aged zebrafish brains. It implied the involvement of microglia and T cells in the progression of neurodegeneration in aging.
Assuntos
Microglia , Peixe-Zebra , Animais , Encéfalo , Animais Geneticamente Modificados , Neurônios/metabolismoRESUMO
Congenital heart disease (CHD) is the most common birth defect worldwide and a main cause of perinatal and infant mortality. Our previous genome-wide association study identified 53 SNPs that associated with CHD in the Han Chinese population. Here, we performed functional screening of 27 orthologous genes in zebrafish using injection of antisense morpholino oligos. From this screen, 5 genes were identified as essential for heart development, including iqgap2, ptprt, ptpn22, tbck and maml3. Presumptive roles of the novel CHD-related genes include heart chamber formation (iqgap2 and ptprt) and atrioventricular canal formation (ptpn22 and tbck). While deficiency of maml3 led to defective cardiac trabeculation and consequent heart failure in zebrafish embryos. Furthermore, we found that maml3 mutants showed decreased cardiomyocyte proliferation which caused a reduction in cardiac trabeculae due to inhibition of Notch signaling. Together, our study identifies 5 novel CHD-related genes that are essential for heart development in zebrafish and first demonstrates that maml3 is required for Notch signaling in vivo.
Assuntos
Cardiopatias Congênitas , Defeitos dos Septos Cardíacos , Animais , Peixe-Zebra/genética , Estudo de Associação Genômica Ampla , Coração , Cardiopatias Congênitas/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
During coordinated development of two neighboring organs from the same germ layer, how precursors of one organ resist the inductive signals of the other to avoid being misinduced to wrong cell fate remains a general question in developmental biology. The liver and anterior intestinal precursors located in close proximity along the gut axis represent a typical example. Here we identify a zebrafish leberwurst (lbw) mutant with a unique hepatized intestine phenotype, exhibiting replacement of anterior intestinal cells by liver cells. lbw encodes the Cdx1b homeoprotein, which is specifically expressed in the intestine, and its precursor cells. Mechanistically, in the intestinal precursors, Cdx1b binds to genomic DNA at the regulatory region of secreted frizzled related protein 5 (sfrp5) to activate sfrp5 transcription. Sfrp5 blocks the mesoderm-derived, liver-inductive Wnt2bb signal, thus conferring intestinal precursor cells resistance to Wnt2bb. These results demonstrate that the intestinal precursors avoid being misinduced toward hepatic lineages through the activation of the Cdx1b-Sfrp5 cascade, implicating Cdx/Sfrp5 as a potential pharmacological target for the manipulation of intestinal-hepatic bifurcations, and shedding light on the general question of how precursor cells resist incorrect inductive signals during embryonic development.