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PubMed2005

The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans.

The let-7 microRNA is phylogenetically conserved and temporally expressed in many animals. C. elegans let-7 controls terminal differentiation in a stem cell-like lineage in the hypodermis, while human let-7 has been implicated in lung cancer. To elucidate let-7's role in temporal control of nematode development, we used sequence analysis and reverse genetics to identify candidate let-7 target genes. We show that the nuclear hormone receptor daf-12 is a let-7 target in seam cells, while the forkhead transcription factor pha-4 is a target in the intestine. Additional likely targets are the zinc finger protein die-1 and the putative chromatin remodeling factor lss-4. Together with the previous identification of the hunchback ortholog hbl-1 as a let-7 target in the ventral nerve cord, our findings show that let-7 acts in at least three tissues to regulate different transcription factors, raising the possibility of let-7 as a master temporal regulator.

Animals↗
PubMedDate not supplied

MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes.

The protein MDC1/NFBD1 contains a forkhead-associated (FHA) domain and two BRCA1 carboxyl-terminal (BRCT) domains. It interacts with several proteins involved in DNA damage repair and checkpoint signalling, and is phosphorylated in response to DNA damage and during mitosis. Upon treatment of cultured human cells with DNA damaging agents, MDC1/NFBD1 translocates to sites of DNA lesions, where it collaborates with other proteins and with phosphorylated histone H2AX to mediate the accumulation of checkpoint and repair factors into nuclear foci. Down-regulation of MDC1/NFBD1 expression levels by small interfering RNA (siRNA) renders cells hyper-sensitive to DNA damaging agents and leads to defects in cell cycle checkpoint activation and apoptosis. Thus, MDC1/NFBD1 appears to be a key regulator of the DNA damage response in mammalian cells.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

NBS1 and its functional role in the DNA damage response.

Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation, chromosome instability and high frequency of malignancies. Since cellular features partly overlap with those of ataxia-telangiectasia (A-T), NBS was long considered an A-T clinical variant. NBS1, the product of the gene underlying the disease, contains three functional regions: the forkhead-associated (FHA) domain and BRCA1 C-terminus (BRCT) domain at the N-terminus, several SQ motifs (consensus phosphorylation sites by ATM and ATR kinases) at a central region and MRE11-binding region at the C-terminus. NBS1 forms a multimeric complex with hMRE11/hRAD50 nuclease at the C-terminus and recruits or retains them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by ATM in response to DNA damage. The combination of the FHA/BRCT domains has a crucial role for the binding of NBS1 to H2AX. Thereafter, the NBS1 complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates, while it also might be involved in suppression of inter-chromosomal recombination even for V(D)J recombination. These processes collaborate with cell cycle checkpoints to facilitate DNA repair, while defects of these checkpoints in NBS cells are partial in nature. A possible explanation for these moderate defects are the redundancy of multiple checkpoint regulations in vertebrates, or the modulator role of NBS1, in which NBS1 amplifies ATM activation by accumulation of the MRN complex at damaged sites. This molecular link of NBS1 to ATM may explain the phenotypic similarity of NBS to A-T.

Amino Acid Motifs↗
PubMed2004

The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.

Apraxias↗
PubMed2005

Extended longevity and insulin signaling in adipose tissue.

Caloric restriction and leanness have been shown to increase longevity in organisms ranging from yeast to mammals. Adipose tissue seems to be a pivotal organ in the aging process and in determination of lifespan. We have recently shown that fat-specific disruption of the insulin receptor gene is sufficient to increase lifespan in FIRKO mice, suggesting that reduced adiposity, even in the presence of normal or increased food intake, can extend lifespan. The model also suggests a special role for the insulin-signaling pathway in adipose tissue in the longevity process. Reduced fat mass has an impact on the duration of life in several other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends lifespan. Furthermore, sirtuin1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking lifespan to adipose tissue. In the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. The effect of reduced adipose tissue mass on lifespan could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis.

Adipose Tissue↗
PubMed2006

Genetic control of longevity in C. elegans.

The nematode Caenorhabditis elegans has proven to be a very useful tool for studying the genetics of longevity. Over 70 genes have been found to influence lifespan in this worm. Those related to the Ins/IGF signaling pathway are among the best studied and will be focused on in this review. The master regulator of this pathway, the forkhead transcription factor DAF-16, can activate an enhanced life maintenance program in response to environmental and gonadal inputs. DAF-16 up- and downregulates expression of many genes leading to metabolic alterations and increased stress and microbial resistance. This is generally confirmed by biochemical and physiological data. Longevity mutants are not hypometabolic and probably produce more reactive oxygen species than wild type. However, their high antioxidant capacity may result in lower oxidative damage. Enhanced molecular turnover rates may also play a role in their longevity phenotype.

Animals↗
PubMed2005

Identification and characterization of Xenopus laevis homologs of mammalian TRAF6 and its binding protein TIFA.

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) transduces signals from members of the TNFR superfamily and the Toll/IL-1R family, leading to activation of transcription factors such as NFkappaB and AP-1. Genetic disruption of the TRAF6 gene in mice results in various developmental abnormalities during embryogenesis, including osteopetrosis, failure of neural tube closure, defective formation of skin appendices, absence of lymph nodes, and absence of mature thymic epithelial cells. To clarify the effect of TRAF6 in development, we previously identified a TRAF-interacting protein with a forkhead-associated domain (TIFA), which binds and activates TRAF6 upon extracellular stimulation. To understand the physiological roles of TRAF6 and TIFA in early development, we studied these genes in Xenopus laevis. Here, we describe identification of X. laevis homologs of mammalian TRAF6 (XTRAF6) and TIFA (XTIFA). As was the case for the mammalian homologs, overexpression of XTRAF6 or XTIFA activated NFkappaB, whereas XTIFA carrying a mutation that abolishes XTRAF6 binding failed to activate NFkappaB, suggesting that XTIFA activates NFkappaB by binding to XTRAF6. XTIFA and XTRAF6 mRNAs were expressed at similar levels in zygotes from the neurula stage and then increased. Whole-mount in situ hybridization revealed that XTRAF6 mRNA was expressed in the head region and neural tube during the neurula stage, and the expression expanded to the pharyngeal apparatus during the tailbud stage. This localization is consistent with the defective neural tube closure and abnormal thymus organogenesis observed in TRAF6-deficient mice. Our results suggest possible cooperation between XTRAF6 and XTIFA during embryogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

In vitro expanded alloantigen-specific CD4+CD25+ regulatory T cell treatment for the induction of donor-specific transplantation tolerance.

The key goal in clinical transplantation is the induction of donor-specific transplantation tolerance to minimise the morbidity and mortality associated with long-term immunosuppression. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) expressing forkhead transcript factor FoxP3 play a crucial role in the prevention of autoimmunity, and appear to mediate transplantation tolerance, and these cells can have indirect allospecificity for donor antigens. Here we show that self-reactive human CD4(+)CD25(+) Tregs can be subverted into allopeptide-specific cells in vitro and be expanded to large cell numbers, and that similar in vitro expanded murine CD4(+)CD25(+) Tregs with indirect allospecificity were capable of inducing donor-specific experimental transplantation tolerance. These data provide a platform for clinical studies using CD4(+)CD25(+) Tregs with indirect allospecificity as potential reagents for the induction of donor-specific transplantation tolerance.

Adoptive Transfer↗
PubMed2005

Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions.

Genes for functional Ser/Thr protein kinases (STPKs) are ubiquitous in prokaryotic genomes, but little is known about their physiological substrates and their actual involvement in bacterial signal transduction pathways. We report here the identification of GarA (Rv1827), a Forkhead-associated (FHA) domain-containing protein, as a putative physiological substrate of PknB, an essential Ser/Thr protein kinase from Mycobacterium tuberculosis. Using a global proteomic approach, GarA was found to be the best detectable substrate of the PknB catalytic domain in non-denatured whole-cell protein extracts from M. tuberculosis and the saprophyte Mycobacterium smegmatis. Enzymological and binding studies of the recombinant proteins demonstrate that docking interactions between the activation loop of PknB and the C-terminal FHA domain of GarA are required to enable efficient phosphorylation at a single N-terminal threonine residue, Thr22, of the substrate. The predicted amino acid sequence of the garA gene, including both the N-terminal phosphorylation motif and the FHA domain, is strongly conserved in mycobacteria and other related actinomycetes, suggesting a functional role of GarA in putative STPK-mediated signal transduction pathways. The ensuing model of PknB-GarA interactions suggests a substrate recruitment mechanism that might apply to other mycobacterial kinases bearing multiple phosphorylation sites in their activation loops.

Amino Acid Sequence↗
PubMed2006

Partially unfolded forms and non-two-state folding of a beta-sandwich: FHA domain from Arabidopsis receptor kinase-associated protein phosphatase.

FHA domains adopt a beta-sandwich fold with 11 strands. The first evidence of partially unfolded forms of a beta-sandwich is derived from native-state hydrogen exchange (NHX) of the forkhead-associated (FHA) domain from kinase-associated protein phosphatase from Arabidopsis. The folding kinetics of this FHA domain indicate that EX2 behavior prevails at pH 6.3. In the chevron plot, rollover in the folding arm and bends in the unfolding arm suggest folding intermediates. NHX of this FHA domain suggests a core of six most stable beta-strands and two loops, characterized by rare global unfolding events. Flanking this stable core are beta-strands and recognition loops with less stability, termed subglobal motifs. These suggest partially unfolded forms (near-native intermediates) with two levels of stability. The spatial separation of the subglobal motifs on the flanks suggests possible parallelism in their folding as additional beta-strands align with the stable core of six strands. Intermediates may contribute to differences in stabilities and m-values suggested by NHX or kinetics relative to chemical denaturation. Residual structure in the unfolded regime is suggested by superprotection of beta-strand 6 and by GdmCl-dependence of adjustments in amide NMR spectra and residual optical signal. The global folding stability depends strongly on pH, with at least 3 kcal/mol more stability at pH 7.3 than at pH 6.3. This FHA domain is hypothesized to fold progressively with initial hydrophobic collapse of its stable six-stranded core followed by addition of less stable flanking beta-strands and ordering of recognition loops.

Arabidopsis Proteins↗
PubMed2006

Specific interactions of the wing domains of FOXA1 transcription factor with DNA.

FOX (forkhead box) transcription factors have diverse regulatory roles in development, signaling, and longevity, as well as being able to bind stably to target sites in silent chromatin. Crystal structure analysis showed that the FOXA DNA binding domain folds into a helix-turn-helix (HTH) motif flanked on either side by "wings" of polypeptide chain. The wings have the potential to interact with the DNA minor groove along the long axis of the DNA helix, flanking the HTH interactions with the major groove. Diverse FOX family homologs exist, and structural studies with certain DNA target sites suggest that neither of the wing regions are well ordered or provide a stable contribution to DNA target site binding. However, FOXA1 binds certain DNA target sites with high affinity, and as a monomer. To determine whether the wing domains contribute to stable DNA binding, we assessed complexes of FOXA with high and lower affinity DNA target sites by hydroxyl radical footprinting and site-directed mutagenesis. The data revealed clear protections predicted for wing interactions at the high affinity target, but less so at the lower affinity target, indicating that the wing domains stably interact with high affinity DNA sites for FOXA proteins.

Base Sequence↗
PubMed2006

Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway.

We have shown previously that 1alpha, 25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D3 (Gemini) compounds, which have two side chains attached to carbon-20, had increased anti-tumor activities against breast, prostate and leukemia cell lines in comparison to 1,25(OH)2 vitamin D3. This prompted us to synthesize additional Gemini compounds with further modifications and evaluate their anticancer effects. Most effective in this series was 1,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-vitamin D3 [Gemini-23-yne-26,27-hexafluoro-D3]. This analog was approximately 10-fold more potent than previously characterized Gemini compounds in inhibiting the clonal growth of HL-60, MCF-7 and LNCaP cell lines. Also in MCF-7 cells, Gemini-23-yne-26,27-hexafluoro-D3 caused dephosphorylation of the oncogenic kinase, Akt, resulting in dephosphorylation of the Akt target proteins, Forkhead transcription factor and mammalian target of rapamycin (mTOR). Downstream effectors of mTOR were also inhibited by the analog as demonstrated by decreased phosphorylation of both S6 kinase, and the translation inhibitor, 4E-BP1. The mTOR pathway regulates mRNA translation; exposure of MCF-7 cells to Gemini-23-yne-26,27-hexafluoro-D3 decreased their rate of protein synthesis and increased the association of 4EBP-1 with the translation initiation factor, eIF4E. Inhibition of the Akt-mTOR pathway represents a novel mechanism by which vitamin D3 analogs may modulate the expression and activity of proteins involved in cancer cell proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Phosphorylation of PI3K/Akt and MAPK/ERK in an early entry step of enterovirus 71.

Viruses have been known to subvert the anti-apoptotic pathways of the host cell in order to delay apoptosis. However, the mechanisms utilized by enterovirus 71 (EV71) to mediate anti-apoptotic activity remained undetermined. We observed that EV71 infection induced an early activation of both phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK/ERK signaling pathways. The activity of GSK3beta, a downstream target of these pathways, was negatively regulated by the activation of both MAPK/ERK and PI3K/Akt. The phosphorylation of GSK3 could be inhibited by treatment with the specific inhibitors of MAPK/ERK and PI3K/Akt. Other Akt downstream targets, BAD, caspase-9 and the Forkhead transcription factor (FKHR), were not phosphorylated during the course of infection by EV71. We further demonstrated that infection by UV-irradiated, inactivated virus triggered early Akt activation but was insufficient to trigger late Akt activation. These data suggest that with the phosphorylation of MAPK/ERK and PI3K/Akt the subsequent inactivation of GSK3beta is utilized by EV71 as a potential mechanism to delay host cell apoptosis.

Animals↗
PubMed2005

Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation.

The development of age-related proliferative disorders of the prostate gland is supported by transdifferentiation and cellular senescence processes in the stroma. Both processes are involved in remodeling of stromal tissue, as observed in benign prostatic hyperplasia (BPH), and in "reactive stroma" adjacent to prostate cancer (PCa). It has been assumed that TGF-beta1 plays a key role in the aging prostate by inducing premature senescence and favoring myofibroblast differentiation. Therefore, we evaluated the stromal cell phenotypes of human primary adult prostatic fibroblasts (n=3) and the molecular and cellular mechanisms of growth arrest after treatment with TGF-beta1 and of in vitro cellular senescence. Microarray analysis, quantitative PCR, immunofluorescence and western blot revealed that cellular senescence and transdifferentiation of fibroblasts have distinct underlying mechanisms, pathways and gene and protein expression profiles in human PrSCs. In clear contrast to senescent cells, TGF-beta1-treated cells morphologically transdifferentiated into myofibroblasts with dense cytoskeletal fibers and increased expression of smooth muscle cell alpha-actin, calponin and tenascin. TGF-beta1 induced neither expression of senescence-associated markers nor genes involved in terminal growth arrest, such as senescence-associated beta-galactosidase and cyclin-dependent kinase (cdk) inhibitors p16(Ink4A) and p21(Cip1) but increased p15(Ink4B) protein expression. Differentiation inhibitor (Id-1) protein level down-regulation was observed under both conditions. Genes specifically up-regulated by transdifferentiation but not by cellular senescence of PrSCs were metalloproteinase 1 tissue inhibitor (Timp1), transgelin (Tagln), gamma 2 actin (Actg2), plasminogen activator inhibitor 1 (Serpinel), insulin-like growth factor binding protein 3 (Igfbp3), parathyroid hormone-like hormone (Pthlp), Tgfb-1, four and a half LIM domains 2 (Fhl-2), hydrogen peroxide-inducible clone 5 (Hic5) and cartilage oligomeric matrix protein (Comp). Other genes, such as Cdc28 protein kinase 1 (Cks1b), v-myb myeloblastosis viral oncogene homolog (MybL2), pyruvate kinase, muscle 2 (Pkm2) and Forkhead box M1 (FoxM1), were down-regulated only upon TGF-beta1 treatment but not by cellular senescence. Pyruvate dehydrogenase kinase 3 (Pdk3) and connective tissue growth factor (Ctgf) were up-regulated and hyaluronan synthase 3 (Has3) down-regulated under both conditions. Moreover, GageC1, a prostate/testis-specific protein overexpressed in symptomatic BPH and PCa was induced in transdifferentiated stromal cells. Genes such as GageC1 could be promising targets for therapeutic inhibitors of stromal tissue remodeling and progression of BPH and PCa.

Cell Differentiation↗
PubMed2006

Epididymis-specific promoter-driven gene targeting: a transcription factor which regulates epididymis-specific gene expression.

Mammalian spermatozoa undergo several modification and finally acquire the ability to fertilize during epididymal transit. One of the distinct features of the epididymis is that it displays a highly regionalized pattern of gene expression. This tissue-, region-, and cell-specific pattern of gene expression is critical for the maintenance of a fully functional epididymis. One would hypothesize that disrupting this process provides an ideal approach to male contraception, since it would not interfere with testicular endocrine output or sperm production. To achieve this purpose, we studied a cluster of epididymis-specific lipocalin genes for understanding the specific mechanisms involved in the control of gene expression in the epididymis. We have identified six epididymis-specific lipocalin genes that are differently regulated and regionalized in the epididymis. Lipocalin 5 [Lcn5 or epididymal retinoic acid-binding protein (E-RABP)] is a member of this epididymis-specific lipocalin gene cluster, which binds hydrophobic molecules such as retinoic acid. We have previously shown that the 5kb promoter fragment of the Lcn5 gene confers both androgen-dependent regulation and epididymis-specific gene expression in transgenic mice whereas 0.6 kb promoter fragment does not. To further narrow down the important cis-regulatory elements that regulate gene expression in the epididymis, we studied the Lcn5 promoter in both transgenic mice and immortalized epididymal cells. We have found that 1.8kb promoter fragment of the Lcn5 gene was sufficient for tissue- and region-specific expression in transgenic mice, and that a transcription factor Forkhead box A2 (Foxa2) interacts with the androgen receptor and binds to the 100 bp fragment of the Lcn5 promoter between 1.2 and 1.3 kb. Our finding provides a framework for further analysis of the epididymal lipocalin gene regulation and modulated control of epididymis-specific expression.

Animals↗
PubMed2005

Sgk1, a cell survival response in neurodegenerative diseases.

Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases. Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations. These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.

Animals↗
PubMed2005

Control of foot differentiation in Hydra: phylogenetic footprinting indicates interaction of head, bud and foot patterning systems.

Homeodomain transcription factor CnNK-2 seems to play a major role in foot formation in Hydra. Recently, we reported in vitro evidence indicating that CnNK-2 has autoregulatory features and regulates expression of the morphogenetic peptide pedibin. We proposed that CnNK-2 and pedibin synergistically orchestrate foot differentiation processes. Here, we further analyzed the regulatory network controlling foot formation in Hydra. By phylogenetic footprinting we compared the CnNK-2 5'-flanking sequence from two closely related species, Hydra vulgaris and Hydra oligactis. Unexpectedly, we detected a highly conserved binding site for HNF-3beta, a vertebrate Forkhead transcription factor, in the CnNK-2 5'-flanking region. The Hydra HNF-3beta homolog budhead is predominantly expressed in the apical region of the body column and early during budding. Budhead is absent from tissue expressing CnNK-2 and thought to be involved in determining tissue for head differentiation. By electrophoretic mobility shift assays we demonstrate an in vitro interaction between recombinant budhead protein and the interspecific conserved HNF-3beta binding motif in the CnNK-2 5'-flanking region. Our results strengthen the view of CnNK-2 as an important regulator during foot patterning processes. Furtheron, they point to budhead as a candidate for a transcriptional regulator of CnNK-2 and to an interaction of foot and head patterning processes in Hydra on the molecular level.

Animals↗
PubMed2004

Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues.

Members of the Forkhead box (Fox) transcription factors family Foxa1 (Hnf-3 alpha), Foxa2 (Hnf-3 beta) are known to influence gene expression in endodermally derived tissues including lung, liver, pancreas, stomach, and intestine. In the present study, we have generated highly specific antibodies for Foxa1 and Foxa2 and determined their expression patterns in the developing and adult mouse. Foxa1 and Foxa2 were detected in the nuclei of tissues derived from both foregut and hindgut endoderm (liver, lung, pancreas, stomach, intestine, prostate and bladder). Foxa2 and Foxa1 were also detected in organs deriving from ectodermal (several brain structures and olfactory epithelium) and mesodermal origins (kidney, vagina and uterus, seminal and coagulating glands) during development. Colocalization and distinct sites of expression of Foxa1 and Foxa2 indicate unique as well as overlapping roles of Foxa1 or Foxa2 during morphogenesis and in the function of different adult organs.

Adult↗