Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut

Reciprocal inductive signals between the endoderm and mesoderm are critical to vertebrate gut development. Sonic hedgehog encodes a secreted protein known to act as an inductive signal in several regions of the developing embryo. In this report, we provide evidence to support the role of Sonic hedgehog and its target genes Bmp-4 and the Abd-B-related Hox genes in the induction and patterning the chick hindgut. Sonic is expressed in the definitive endoderm at the earliest stage of chick gut formation. Immediately subjacent to Sonic expression in the caudal endoderm is undifferentiated mesoderm, later to become the visceral mesoderm of the hindgut. Genes expressed within this tissue include Bmp-4 (a TGF-beta relative implicated in proper growth of visceral mesoderm) and members of the Abd-B class of Hox genes (known regulators of pattern in many aspects of development). Using virally mediated misexpression, we show that Sonic hedgehog is sufficient to induce ectopic expression of Bmp-4 and specific Hoxd genes within the mesoderm. Sonic therefore appears to act as a signal in an epithelial-mesenchymal interaction in the earliest stages of chick hindgut formation. Gut pattern is evidenced later in gut morphogenesis with the presence of anatomic boundaries reflecting phenotypically and physiologically distinct regions. The expression pattern of the Abd-b-like Hox genes remains restricted in the hindgut and these Hox expression domains reflect gut morphologic boundaries. This finding strongly supports a role for these genes in determining the adult gut phenotype. Our results provide the basis for a model to describe molecular controls of early vertebrate hindgut development and patterning. Expression of homologous genes in Drosophila suggest that aspects of gut morphogenesis may be regulated by similar inductive networks in the two organisms.

Download Full-text

zfh-1 is required for germ cell migration and gonadal mesoderm development in Drosophila

Development ◽

10.1242/dev.125.4.655 ◽

1998 ◽

Vol 125 (4) ◽

pp. 655-666 ◽

Cited By ~ 19

Author(s):

H.T. Broihier ◽

L.A. Moore ◽

M. Van Doren ◽

S. Newman ◽

R. Lehmann

Keyword(s):

Cell Migration ◽

Germ Cell ◽

Germ Cells ◽

Ectopic Expression ◽

Homeodomain Protein ◽

Mesoderm Development ◽

Visceral Mesoderm ◽

Temporal Course ◽

Germ Cell Migration

In Drosophila as well as many vertebrate systems, germ cells form extraembryonically and migrate into the embryo before navigating toward gonadal mesodermal cells. How the gonadal mesoderm attracts migratory germ cells is not understood in any system. We have taken a genetic approach to identify genes required for germ cell migration in Drosophila. Here we describe the role of zfh-1 in germ cell migration to the gonadal mesoderm. In zfh-1 mutant embryos, the initial association of germ cells and gonadal mesoderm is blocked. Loss of zfh-1 activity disrupts the development of two distinct mesodermal populations: the caudal visceral mesoderm and the gonadal mesoderm. We demonstrate that the caudal visceral mesoderm facilitates the migration of germ cells from the endoderm to the mesoderm. Zfh-1 is also expressed in the gonadal mesoderm throughout the development of this tissue. Ectopic expression of Zfh-1 is sufficient to induce additional gonadal mesodermal cells and to alter the temporal course of gene expression within these cells. Finally, through analysis of a tinman zfh-1 double mutant, we show that zfh-1 acts in conjunction with tinman, another homeodomain protein, in the specification of lateral mesodermal derivatives, including the gonadal mesoderm.

Download Full-text

Abstract 2178: Sonic Hedgehog In Adult Hypoxic Cerebellum

Circulation ◽

10.1161/circ.116.suppl_16.ii_472-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Giuseppe Straface ◽

Andrea Flex ◽

Federico Biscetti ◽

Eleonora Gaetani ◽

Giovanni Pecorini ◽

...

Keyword(s):

Sonic Hedgehog ◽

Target Genes ◽

Positive Staining ◽

Lacz Gene ◽

Downstream Target ◽

Shh Pathway ◽

And Migration ◽

First Time ◽

Proliferation And Migration

Background: Cerebellar hypoxia is responsible for important aspects of cognitive deterioration and motor disturbances in neurological disorders, such as stroke, vascular dementia, and neurodegeneration. In the cerebellum, VEGF is significantly upregulated after hypoxia and is able to induce angiogenesis, reduce neuronal apoptosis, and regulate neuronal differentiation, proliferation, and migration. But, VEGF is not sufficient to provide neuroprotection. A crucial role is played by growth associated protein-43 (GAP43), for which important activities have been described. The purpose of this study was to investigate the role of the developmental Sonic hedgehog (Shh) signaling pathway in postnatal hypoxic cerebellum and its relationship with VEGF and GAP43 expression. Methods: We used adult C57BL/6J mice, ptc1-lacZ mice, and GAP43−/− mice for these experiments. Ptc1-lacZ mice carry a non-disruptive insertion of the lacZ gene under the control of the ptc1 promoter. Ptc1 is a downstream-transcriptional target of Shh and its upregulation indicates activation of the Shh pathway. Mice were exposed to systemic normobaric hypoxia (6%O 2 ) for 6 hours and the expression of Shh, Ptc1, VEGF, and GAP43 were investigated. Results: After exposure to hypoxia, Shh-positive staining was detected in Purkinje cells (PCs). The same cells were also lacZ(ptc1)-positive, indicating that PCs are both Shh-producing and -responding elements. Also the cells of the internal granular layer (IGL) were lacZ(ptc1)-positive, indicating that these cells are Shh-responsive. LacZ(ptc1)-positive IGL cells were also immunopositive for VEGF and GAP-43. We also found that ptc1 expression is lost in PCs of GAP43−/− mice, indicating that Shh requires GAP43 to activate its downstream target genes in PCs. Finally, when cultures enriched in granular cells were stimulated with Shh recombinant protein, GAP43 phosphorylation was increased. This effect was inhibited by Shh-inhibitor cyclopamine. Conclusions: This is the first time that hypoxia is reported to activate the Shh pathway in the adult. Our data suggest that the Shh pathway might be important for the cerebellar response to hypoxia, through interactions with VEGF and GAP43.

Download Full-text

The Mir-17-92 Cluster Contributes to MLL Leukemia through the Repression of PKNOX1, a MEIS1 Competitor

Blood ◽

10.1182/blood.v124.21.877.877 ◽

2014 ◽

Vol 124 (21) ◽

pp. 877-877

Author(s):

Yousaf A Mian ◽

Nancy J. Zeleznik-Le

Keyword(s):

Target Genes ◽

Hox Genes ◽

Regulatory Mechanism ◽

Conflicts Of Interest ◽

Chromosome Translocation ◽

Transcriptional Elongation ◽

Terminal Portion ◽

Partner Protein ◽

Carboxy Terminal

Abstract Leukemias which arise as a result of translocations between the MLL gene and one of more than 80 different partner genes have a relatively poor prognosis. As a result of chromosome translocation, the carboxy-terminal portion of MLL containing the H3K4 methyltransferase domain is replaced by partner protein domains. In most cases this causes constitutive recruitment of transcriptional elongation machinery to MLL target genes. Downstream targets of MLL are aberrantly upregulated and include developmentally important HOX genes and MEIS1, as well as multiple microRNAs. Here we examine the contribution of specific miRNAs in the miR-17-92 cluster to MLL leukemia through the use of custom antagomiR oligonucleotides. Combinatorial treatment with antagomiRs against miR-17 and miR-19a dramatically reduce colony forming ability of MLL-fusion containing cells, but not non-MLL AML controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17 and miR-19a. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX proteins. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of Pknox1 to leukemia in a murine MLL-AF9 model. Collectively, these data implicate the miR-17-92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia. This approach represents a paradigm where targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen. Disclosures No relevant conflicts of interest to declare.

Download Full-text

The Mesodermal Expression of rolling stone (rost) Is Essential for Myoblast Fusion in Drosophila and Encodes a Potential Transmembrane Protein

The Journal of Cell Biology ◽

10.1083/jcb.138.2.337 ◽

1997 ◽

Vol 138 (2) ◽

pp. 337-348 ◽

Cited By ~ 17

Author(s):

Achim Paululat ◽

Anette Goubeaud ◽

Christine Damm ◽

Stefan Knirr ◽

Susanne Burchard ◽

...

Keyword(s):

Transmembrane Protein ◽

Myoblast Fusion ◽

Fusion Process ◽

Knock Out ◽

Visceral Mesoderm ◽

Homologous Genes ◽

Rolling Stone ◽

Embryonic Nervous System ◽

Drosophila Embryos

In homozygous rolling stone embryos, the fusion of myoblasts to syncytial myotubes is diminished. Nevertheless, the visceral mesoderm, the heart mesoderm, and few somatic muscles are properly formed. Thus, we postulate a central role of rolling stone for the fusion process within the somatic mesoderm. We have cloned the rolling stone gene, and the deduced protein sequence is in accordance with a transmembrane protein, which agrees with the enrichment of Rost in the membrane fraction of Drosophila embryos. No homologous genes have been described so far. rolling stone is expressed in the embryonic nervous system and cells of the somatic mesoderm, most notable in muscle founder cells. To elucidate the function of rolling stone for myoblast fusion, we applied a knock-out strategy. The expression of an antisense rolling stone transcript specifically within the mesoderm of wild-type embryos results in fusion defects of myoblasts, proving that the rolling stone expression in the mesoderm is responsible for the rolling stone phenotype. We suggest that rolling stone is a member of a group of genes that are necessary for the fusion process during myogenesis.

Download Full-text

The role of brinker in mediating the graded response to Dpp in early Drosophila embryos

Development ◽

10.1242/dev.126.15.3323 ◽

1999 ◽

Vol 126 (15) ◽

pp. 3323-3334 ◽

Cited By ~ 11

Author(s):

A. Jazwinska ◽

C. Rushlow ◽

S. Roth

Keyword(s):

Target Gene ◽

Target Genes ◽

Gene Activation ◽

Ectopic Expression ◽

Intermediate Level ◽

Graded Response ◽

High Level ◽

Drosophila Embryos ◽

Novel Protein

Brinker (Brk), a novel protein with features of a transcriptional repressor, regulates the graded response to Decapentaplegic (Dpp) in appendage primordia of Drosophila. Here, we show that in the embryo brk also has differential effects on Dpp target genes, depending on the level of Dpp activity required for their activation. Low-level target genes, like dpp itself, tolloid and early zerknullt, show strong ectopic expression in ventrolateral regions of brk mutant embryos; intermediate-level target genes like pannier show weak ectopic expression, while high-level target genes like u-shaped and rhomboid are not affected. Ectopic target gene activation in the absence of brk is independent of Dpp, Tkv and Medea, indicating that Dpp signaling normally antagonizes brk's repression of these target genes. brk is expressed like short gastrulation (sog) in ventrolateral regions of the embryo abutting the dpp domain. Here, both brk and sog antagonize the antineurogenic activity of Dpp so that only in brk sog double mutants is the neuroectoderm completely deleted.

Download Full-text

Role of Hox genes in regulating digit patterning

The International Journal of Developmental Biology ◽

10.1387/ijdb.180200mr ◽

2018 ◽

Vol 62 (11-12) ◽

pp. 797-805 ◽

Cited By ~ 4

Author(s):

Rocío Pérez-Gómez ◽

Endika Haro ◽

Marc Fernández-Guerrero ◽

María F. Bastida ◽

María A. Ros

Keyword(s):

Sonic Hedgehog ◽

Selection Pressure ◽

Distal Part ◽

Hox Genes ◽

Extensive Study ◽

Functional Adaptation ◽

Digit Number ◽

Hox Proteins ◽

Self Organizing

The distal part of the tetrapod limb, the autopod, is characterized by the presence of digits. The digits display a wide diversity of shapes and number reflecting selection pressure for functional adaptation. Despite extensive study, the different aspects of digit patterning, as well as the factors and mechanisms involved are not completely understood. Here, we review the evidence implicating Hox proteins in digit patterning and the interaction between Hox genes and the Sonic hedgehog/Gli3 pathway, the other major regulator of digit number and identity. Currently, it is well accepted that a self-organizing Turing-type mechanism underlies digit patterning, this being understood as the establishment of an iterative arrangement of digit/interdigit in the hand plate. We also discuss the involvement of 5’ Hox genes in regulating digit spacing in the digital plate and therefore the number of digits formed in this self-organizing system.

Download Full-text

CircPTPRA blocks the recognition of RNA N6-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression

Molecular Cancer ◽

10.1186/s12943-021-01359-x ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Fei Xie ◽

Chao Huang ◽

Feng Liu ◽

Hui Zhang ◽

Xingyuan Xiao ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Ectopic Expression ◽

Migration And Invasion ◽

Circular Rnas ◽

Clinical Role ◽

Rna Immunoprecipitation

Abstract Background Circular RNAs (circRNAs) have been found to have significant impacts on bladder cancer (BC) progression through various mechanisms. In this study, we aimed to identify novel circRNAs that regulate the function of IGF2BP1, a key m6A reader, and explore the regulatory mechanisms and clinical significances in BC. Methods Firstly, the clinical role of IGF2BP1 in BC was studied. Then, RNA immunoprecipitation sequencing (RIP-seq) analysis was performed to identify the circRNAs interacted with IGF2BP1 in BC cells. The overall biological roles of IGF2BP1 and the candidate circPTPRA were investigated in both BC cell lines and animal xenograft studies. Subsequently, we evaluated the regulation effects of circPTPRA on IGF2BP1 and screened out its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circPTPRA might act as a blocker in recognition of m6A. Results We demonstrated that IGF2BP1 was predominantly binded with circPTPRA in the cytoplasm in BC cells. Ectopic expression of circPTPRA abolished the promotion of cell proliferation, migration and invasion of BC cells induced by IGF2BP1. Importantly, circPTPRA downregulated IGF2BP1-regulation of MYC and FSCN1 expression via interacting with IGF2BP1. Moreover, the recognition of m6A-modified RNAs mediated by IGF2BP1 was partly disturbed by circPTPRA through its interaction with KH domains of IGF2BP1. Conclusions This study identifies exonic circular circPTPRA as a new tumor suppressor that inhibits cancer progression through endogenous blocking the recognition of IGF2BP1 to m6A-modified RNAs, indicating that circPTPRA may serve as an exploitable therapeutic target for patients with BC.

Download Full-text

DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as an Alk target in the Drosophila visceral mesoderm

Development ◽

10.1242/dev.199465 ◽

2021 ◽

Vol 148 (23) ◽

Author(s):

Patricia Mendoza-Garcia ◽

Swaraj Basu ◽

Sanjay Kumar Sukumar ◽

Badrul Arefin ◽

Georg Wolfstetter ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Transcriptional Profiling ◽

Rtk Signaling ◽

Visceral Mesoderm ◽

Anaplastic Lymphoma ◽

Mrna And Protein Expression ◽

Target Molecules ◽

Target Binding

ABSTRACT Development of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.

Download Full-text

Hox genes in the coordination of embryonic development. Model of hourglass in the description of vertebrate ontogenesis

Journal of Education, Health and Sport ◽

10.12775/jehs.2021.11.12.002 ◽

2021 ◽

Vol 11 (12) ◽

pp. 24-37

Author(s):

Sergey Dolomatov ◽

Vera Kazakova ◽

Walery Zukow

Keyword(s):

Embryonic Development ◽

Tissue Regeneration ◽

Target Genes ◽

Hox Genes ◽

Development Model ◽

Tissue Morphogenesis ◽

Hox Proteins ◽

Temporal And Spatial

The paper analyzes the role of HOX genes in the processes of embryonic development of vertebrates. Based on the analysis, it is concluded that HOX genes are the most important regulators of embryonic development. The HOX genes predominantly realize their influence through specific HOX proteins that have the ability to regulate the expression of target genes. The order of expression of the HOX genes, as a rule, obeys the rule of temporal and spatial colinearity. This mechanism determines the temporal and spatial course of tissue morphogenesis during embryonic development and tissue regeneration in organisms that have reached the stage of maturity. The process of embryo morphogenesis, determined by highly conserved HOX genes, explains the appearance of the phylotypic period - the stage of embryonic development of vertebrates, at which embryos of different classes of vertebrates have distinct morphological similarities.

Download Full-text

Ectopic Expression of Os-miR408 Improves Thermo-Tolerance of Perennial Ryegrass

Agronomy ◽

10.3390/agronomy11101930 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1930

Author(s):

Geli Taier ◽

Nan Hang ◽

Tianran Shi ◽

Yanrong Liu ◽

Wenxin Ye ◽

...

Keyword(s):

Heat Stress ◽

High Temperature ◽

Perennial Ryegrass ◽

Target Genes ◽

Morphological Changes ◽

Ectopic Expression ◽

Plant Tolerance ◽

Cool Season ◽

Positive Role

With global warming, high temperature stress has become a main threat to the growth of cool-season turfgrasses, including perennial ryegrass. As one of the conserved plant microRNA families, miR408s are known to play roles in various abiotic stresses, including cold, drought, salinity, and oxidative stress, but no report, thus far, was found for heat. Here, perennial ryegrass plants overexpressing rice Os-miR408 were used to investigate the role of miR408 in plant heat tolerance. Both wild type (WT) and miR408 transgenic perennial ryegrass plants (TG) were subjected to short-term heat stress at 38 °C for 72 h (experiment 1) or at 42 °C for 48 h (experiment 2), and then let recover for 7 days at optimum temperature. Morphological changes and physiological parameters, including antioxidative responses of TG and WT plants, were compared. The results showed that miR408 downregulated the expression of two putative target genes, PLASTOCYANIN and LAC3. Additionally, overexpression of Os-miR408 improved thermo-tolerance of perennial ryegrass, demonstrated by lower leaf lipid peroxidation and electrolyte leakage, and higher relative water content after both 38 and 42 °C heat stresses. In addition, the enhanced thermotolerance of TG plants could be associated with its morphological changes (e.g., narrower leaves, smaller tiller angles) and elevated antioxidative capacity. This study is the first that experimentally reported a positive role of miR408 in plant tolerance to heat stress, which provided useful information for further understanding the mechanism by which miR408 improved plant high-temperature tolerance, and offered a potential genetic resource for breeding heat-resistant cool-season turfgrass in the future.

Download Full-text