Mutational analysis of the Drosophila tolloid gene, a human BMP-1 homolog

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 861-870 ◽  
Author(s):  
A.L. Finelli ◽  
C.A. Bossie ◽  
T. Xie ◽  
R.W. Padgett
Keyword(s):  
Cell Fate ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mutational Analysis ◽  
Genetic Interaction ◽  
Missense Mutations ◽  
Regulatory Domains ◽  
Protein Functions ◽  
Dorsal Cells ◽  
Dorsal Cell Fate

Seven zygotically active genes have been identified in Drosophila that determine the fate of dorsal cells in the developing embryo. decapentaplegic (dpp), a member of the transforming growth factor-beta (TGF-beta) family, appears to play the central role in dorsal ectoderm formation, as mutations in this gene confer the most severe mutant phenotype of this group of genes. dpp's activity is modulated by tolloid, which also has a role in the determination of dorsal cell fate. tolloid encodes a protein that contains a metalloprotease domain and regulatory domains consisting of two EGF motifs and five C1r/s repeats. We have generated several mutant tolloid alleles and have examined their interaction with a graded set of dpp point alleles. Some tolloid alleles act as dominant enhancers of dpp in a trans heterozygote, and are therefore antimorphic alleles. However, a tolloid deficiency shows no such genetic interaction. To characterize the nature of the tolloid mutations, we have sequenced eighteen tolloid alleles. We find that five of the seven alleles that act as dominant enhancers of dpp are missense mutations in the protease domain. We also find that most tolloid alleles that do not interact with dpp are missense mutations in the C-terminal EGF and C1r/s repeats, or encode truncated proteins that delete these repeats. Based on these data, we propose a model in which the tolloid protein functions by forming a complex containing DPP via protein-interacting EGF and C1r/s domains, and that the protease activity of TOLLOID is necessary, either directly or indirectly, for the activation of the DPP complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Basic FGF and TGF-beta 1 influence commitment to melanogenesis in neural crest-derived cells of avian embryos

Development ◽  
1991 ◽  
Vol 111 (2) ◽  
pp. 635-645 ◽  
Author(s):  
K.M. Stocker ◽  
L. Sherman ◽  
S. Rees ◽  
G. Ciment
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Neural Crest ◽  
Cell Fate ◽  
Transforming Growth Factor Beta ◽  
Culture Medium ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Pigment Cells ◽  
Tgf Beta

In previous studies, we showed that neural crest (NC)-derived cells from embryonic quail dorsal root ganglia (DRG) and peripheral nerve (PN), which do not normally give rise to melanocytes, become committed to melanogenesis following treatment in culture with the phorbol ester drug 12-O-tetradecanoyl phorbol-13-acetate (TPA). These and other observations support the notion that melanocytes and Schwann cells are derived from a common bipotent intermediate in the neural crest lineage—the melanocyte/Schwann cell progenitor. In this study, we test the possibility that peptide growth factors found in the embryonic environment might act similarly to TPA to influence the fates of these cells. DRG and PN explants were cultured in medium supplemented with a variety of growth factors, and then the cultures were examined for the presence of pigment cells. We found that basic fibroblast growth factor (bFGF), but not various other growth factors, induced pigmentation in about 20% of these cultures. When low concentrations of TPA were included in the culture medium, bFGF augmented the TPA-induced pigmentation, significantly increasing the proportion of pigmented cultures. These effects of bFGF were age-dependent, and could be blocked by addition of a bFGF-neutralizing antibody to the culture medium. In contrast to these stimulatory effects of bFGF, transforming growth factor-beta 1 (TGF-beta 1) was found to inhibit the TPA- or bFGF-induced pigmentation of DRG cultures. These data suggest, therefore, that at least some NC-derived cells are responsive to bFGF and TGF-beta 1, and that these growth factors may play an important role in the control of NC cell fate.

In vivo analysis using variants of zebrafish BMPR-IA: range of action and involvement of BMP in ectoderm patterning

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 181-190 ◽  
Author(s):  
M. Nikaido ◽  
M. Tada ◽  
H. Takeda ◽  
A. Kuroiwa ◽  
N. Ueno
Keyword(s):  
Cell Fate ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Ectopic Expression ◽  
Signal Propagation ◽  
Early Embryo ◽  
Type I ◽  
Cell Fate Conversion

It has been an intriguing problem whether the polypeptide growth factors belonging to the transforming growth factor-beta (TGF-beta) superfamily function as direct and long-range signaling molecules in pattern formation of the early embryo. In this study, we examined the mechanism of signal propagation of bone morphogenetic protein (BMP) in the ectodermal patterning of zebrafish embryos, in which BMP functions as an epidermal inducer and a neural inhibitor. To estimate the effective range of zbmp-2, we first performed whole-mount in situ hybridization analysis. The zbmp-2-expressing domain and the neuroectoderm, marked by otx-2 expression, were complementary, suggesting that BMP has a short-range effect in vivo. Moreover, mosaic experiments using a constitutively active form of a zebrafish BMP type I receptor (CA-BRIA) demonstrated that the cell-fate conversion, revealed by ectopic expression of gata-3 and repression of otx-2, occurred in a cell-autonomous manner, denying the involvement of the relay mechanism. We also found that zbmp-2 was induced cell autonomously within the transplanted cells in the host ectoderm, suggesting that BMP cannot influence even the neighboring cells. This result is consistent with the observation that there is no gap between the expression domains of zbmp-2 and otx-2. Taken together, we propose that, in ectodermal patterning, BMP exerts a direct and cell-autonomous effect to fate uncommitted ectodermal cells to become epidermis.

scholarly journals Headcase is a Repressor of Lamellocyte Fate in Drosophila melanogaster

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 173 ◽  
Author(s):  
Gergely I. B. Varga ◽  
Gábor Csordás ◽  
Gyöngyi Cinege ◽  
Ferenc Jankovics ◽  
Rita Sinka ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Cell Differentiation ◽  
Blood Cell ◽  
Cell Fate ◽  
Blood Cells ◽  
Mutational Analysis ◽  
Genetic Interaction ◽  
Lymph Gland ◽  
Loss Of Function ◽  
Hematopoietic Stem

Due to the evolutionary conservation of the regulation of hematopoiesis, Drosophila provides an excellent model organism to study blood cell differentiation and hematopoietic stem cell (HSC) maintenance. The larvae of Drosophila melanogaster respond to immune induction with the production of special effector blood cells, the lamellocytes, which encapsulate and subsequently kill the invader. Lamellocytes differentiate as a result of a concerted action of all three hematopoietic compartments of the larva: the lymph gland, the circulating hemocytes, and the sessile tissue. Within the lymph gland, the communication of the functional zones, the maintenance of HSC fate, and the differentiation of effector blood cells are regulated by a complex network of signaling pathways. Applying gene conversion, mutational analysis, and a candidate based genetic interaction screen, we investigated the role of Headcase (Hdc), the homolog of the tumor suppressor HECA in the hematopoiesis of Drosophila. We found that naive loss-of-function hdc mutant larvae produce lamellocytes, showing that Hdc has a repressive role in effector blood cell differentiation. We demonstrate that hdc genetically interacts with the Hedgehog and the Decapentaplegic pathways in the hematopoietic niche of the lymph gland. By adding further details to the model of blood cell fate regulation in the lymph gland of the larva, our findings contribute to the better understanding of HSC maintenance.

Mutations of the TGFBR2 gene in Chinese patients with Marfan-related syndrome

2010 ◽  
Vol 33 (1) ◽  
pp. 14 ◽  
Author(s):  
JinLan Chen ◽  
BuYun Li ◽  
YiFeng Yang ◽  
JianGuo Hu ◽  
TianLi Zhao ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Chinese Patients ◽  
Silent Mutation ◽  
Missense Mutations ◽  
Coding Region ◽  
Blood Leukocytes ◽  
Growth Factor Beta ◽  
Rare Snp ◽  
Genetic Analyzer

Purpose: Transforming growth factor beta receptors II gene (TGFBR2) mutations associated with Marfan syndrome and Marfan-associated disorders have been investigated. However, such studies are limited in China. To obtain more information about TGFBR2 mutations, we analyzed 6 unrelated Chinese patients with Marfan-associated disorders and without ocular manifestation. Methods: The genomic DNA from blood leukocytes of these 6 patients and their relatives was isolated, and the entire coding region of TGFBR2 was amplified using PCR. We determined the sequence of TGFBR2 with the ABI 3100 Genetic Analyzer. Results: Three mutations were identified in TGFBR2. Two mutations were associated with Loeys-Dietz syndrome (LDS), which were distributed as following: one missense mutation R528C (caused by a 1582C > T substitution) and one polymorphism T315M (a rare SNP). The third mutation was a novel silent mutation associated with MFS2, which was K291K caused by an 873 C > T substitution. Conclusions: The TGFBR2 gene missense mutations are possibly causative mutations of Loeys-Dietz syndrome. This result suggests an increase in the mutation spectrum of Marfan-related disorders in China and possibly world-wide.

scholarly journals Wnt/β-catenin signaling is an evolutionarily conserved determinant of chordate dorsal organizer

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Iryna Kozmikova ◽  
Zbynek Kozmik
Keyword(s):  
Cell Fate ◽  
Current View ◽  
Specific Gene ◽  
Axis Formation ◽  
Dependent Manner ◽  
Evolutionarily Conserved ◽  
Dorsal Axis ◽  
Dorsal Cells ◽  
Dorsal Cell Fate

Deciphering the mechanisms of axis formation in amphioxus is a key step to understanding the evolution of chordate body plan. The current view is that Nodal signaling is the only factor promoting the dorsal axis specification in the amphioxus, whereas Wnt/β-catenin signaling plays no role in this process. Here, we re-examined the role of Wnt/βcatenin signaling in the dorsal/ventral patterning of amphioxus embryo. We demonstrated that the spatial activity of Wnt/β-catenin signaling is located in presumptive dorsal cells from cleavage to gastrula stage, and provided functional evidence that Wnt/β-catenin signaling is necessary for the specification of dorsal cell fate in a stage-dependent manner. Microinjection of Wnt8 and Wnt11 mRNA induced ectopic dorsal axis in neurulae and larvae. Finally, we demonstrated that Nodal and Wnt/β-catenin signaling cooperate to promote the dorsal-specific gene expression in amphioxus gastrula. Our study reveals high evolutionary conservation of dorsal organizer formation in the chordate lineage.

scholarly journals msh specifies dorsal cell fate in the Drosophila wing

Development ◽  
2001 ◽  
Vol 128 (17) ◽  
pp. 3263-3268 ◽  
Author(s):  
Marco Milán ◽  
Ulrich Weihe ◽  
Stanley Tiong ◽  
Welcome Bender ◽  
Stephen M. Cohen
Keyword(s):  
Cell Fate ◽  
Imaginal Disc ◽  
Homeobox Gene ◽  
Wing Imaginal Disc ◽  
Wing Development ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Signaling Center ◽  
Dorsal Cells ◽  
Dorsal Cell Fate

Drosophila limbs develop from imaginal discs that are subdivided into compartments. Dorsal-ventral subdivision of the wing imaginal disc depends on apterous activity in dorsal cells. Apterous protein is expressed in dorsal cells and is responsible for (1) induction of a signaling center along the dorsal-ventral compartment boundary (2) establishment of a lineage restriction boundary between compartments and (3) specification of dorsal cell fate. Here, we report that the homeobox gene msh (muscle segment homeobox) acts downstream of apterous to confer dorsal identity in wing development.

scholarly journals Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers

2002 ◽  
Vol 28 (2) ◽  
pp. 137-148 ◽  
Author(s):  
S Vejda ◽  
M Cranfield ◽  
B Peter ◽  
SL Mellor ◽  
N Groome ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Future Studies ◽  
Adult Rat ◽  
Growth Factor Beta ◽  
Proper Functions ◽  
Balance Family

Activins are cytokines of the transforming growth factor beta family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin betaA, betaB, betaC and betaE subunits in the adult rat and analyzed the composition of putative activin beta dimers. By dissecting tissue distribution of various activins, we found that the liver, in particular the hepatocytes, is the major source for activin betaC and betaE transcripts, since other tissues almost failed to express these isoforms. In sharp contrast, the emergence of activin betaA and betaB appeared ubiquitous. Using a highly selective proteome approach, we were able to identify homo- as well as heterodimers of individual activin subunits, indicating a high redundancy of ligand composition. Certainly, this broad potential to homo- and heterodimerize has to be considered in future studies on activin function.

scholarly journals Targeted Disruption of Tgif, the Mouse Ortholog of a Human Holoprosencephaly Gene, Does Not Result in Holoprosencephaly in Mice

2005 ◽  
Vol 25 (9) ◽  
pp. 3639-3647 ◽  
Author(s):  
Jun Shen ◽  
Christopher A. Walsh
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Missense Mutations ◽  
Targeted Deletion ◽  
Spatiotemporal Expression ◽  
Organ Systems ◽  
Evolutionarily Conserved ◽  
Major Organ

ABSTRACT 5′-TG-3′-interacting factor or transforming growth factor beta (TGF-β)-induced factor (TGIF) belongs to a family of evolutionarily conserved proteins that are characterized by an atypical three-amino-acid loop extension homeodomain. In vitro studies have implicated TGIF as a transcriptional repressor and corepressor in retinoid and TGF-β signaling pathways that regulate several important biological processes. Heterozygous nonsense and missense mutations of the human TGIF gene have been associated with holoprosencephaly, the most common congenital malformation of the forebrain. In mice, Tgif mRNA is expressed ubiquitously in the ventricular neuroepithelium at embryonic day 10.5 (E10.5) but displays a medial to lateral gradient in the developing cerebral cortex at E12.5. The expression quickly declines by E14.5. The spatiotemporal expression profile of Tgif is consistent with its involvement in midline forebrain development. To better understand the function of Tgif in forebrain patterning and proliferation in vivo, we generated mice lacking Tgif by targeted deletion of exons 2 and 3, which encode 98% of the amino acids. Tgif − / − mice had no detectable Tgif protein by Western blotting. Surprisingly, however, these mice were viable and fertile. In addition, there were no discernible derangements in any of the major organ systems, including the forebrain. Overall our results point to a possible functional redundancy of Tgif, potentially provided by the closely related Tgif2.

scholarly journals Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila.

Genetics ◽  
1995 ◽  
Vol 139 (1) ◽  
pp. 241-254 ◽  
Author(s):  
L A Raftery ◽  
V Twombly ◽  
K Wharton ◽  
W M Gelbart
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Genetic Interaction ◽  
Early Embryo ◽  
Loss Of Function ◽  
Morphogenetic Protein ◽  
Imaginal Disks ◽  
Novel Alleles ◽  
Mutant Phenotypes

Abstract Pathways for regulation of signaling by transforming growth factor-beta family members are poorly understood at present. The best genetically characterized member of this family is encoded by the Drosophila gene decapentaplegic (dpp), which is required for multiple events during fly development. We describe here the results of screens for genes required to maximize dpp signaling during embryonic dorsal-ventral patterning. Screens for genetic interactions in the zygote have identified an allele of tolloid, as well as two novel alleles of screw, a gene recently shown to encode another bone morphogenetic protein-like polypeptide. Both genes are required for patterning the dorsalmost tissues of the embryo. Screens for dpp interactions with maternally expressed genes have identified loss of function mutations in Mothers against dpp and Medea. These mutations are homozygous pupal lethal, engendering gut defects and severely reduced imaginal disks, reminiscent of dpp mutant phenotypes arising during other dpp-dependent developmental events. Genetic interaction phenotypes are consistent with reduction of dpp activity in the early embryo and in the imaginal disks. We propose that the novel screw mutations identified here titrate out some component(s) of the dpp signaling pathway. We propose that Mad and Medea encode rate-limiting components integral to dpp pathways throughout development.

scholarly journals Evaluation of the Genetic Variation Spectrum Related to Corneal Dystrophy in a Large Cohort

2021 ◽  
Vol 9 ◽  
Author(s):  
Wei Li ◽  
Ning Qu ◽  
Jian-Kang Li ◽  
Yu-Xin Li ◽  
Dong-Ming Han ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Eye Diseases ◽  
Large Cohort ◽  
Missense Mutations ◽  
High Quality ◽  
Specific Level ◽  
Ethnic Chinese ◽  
Pathogenic Mutations ◽  
Recurrent Mutations

AimsTo characterize the genetic landscape and mutation spectrum of patients with corneal dystrophies (CDs) in a large Han ethnic Chinese Cohort with inherited eye diseases (IEDs).MethodsRetrospective study. A large IED cohort was recruited in this study, including 69 clinically diagnosed CD patients, as well as other types of eye diseases patients and healthy family members as controls. The 792 genes on the Target_Eye_792_V2 chip were used to screen all common IEDs in our studies, including 22 CD-related genes.ResultsWe identified 2334 distinct high-quality variants on 22 CD-related genes in a large IEDs cohort. A total of 21 distinct pathogenic or likely pathogenic mutations were identified, and the remaining 2313 variants in our IED cohort had no evidence of CD-related pathogenicity. Overall, 81.16% (n = 56/69) of CD patients received definite molecular diagnoses, and transforming growth factor-beta-induced protein (TGFBI), CHTS6, and SLC4A11 genes covered 91.07, 7.14, and 1.79% of the diagnosed cases, respectively. Twelve distinct disease-associated mutations in the TGFBI gene were identified, 11 of which were previously reported and one is novel. Four of these TGFBI mutations (p.D123H, p.M502V, p.P501T, and p.P501A) were redefined as likely benign in our Han ethnic Chinese IED cohort after performing clinical variant interpretation. These four TGFBI mutations were detected in asymptomatic individuals but not in CD patients, especially the previously reported disease-causing mutation p.P501T. Among 56 CD patients with positive detected mutations, the recurrent TGFBI mutations were p.R124H, p.R555W, p.R124C, p.R555Q, and p.R124L, and the proportions were 32.14, 19.64, 14.29, 10.71, and 3.57%, respectively. Twelve distinct pathogenic or likely pathogenic mutations of CHTS6 were detected in 28 individuals. The recurrent mutations were p.Y358H, p.R140X, and p.R205W, and the proportions were 25.00, 21.43, and 14.29%, respectively. All individuals associated with TGFBI were missense mutations; 74.19% associated with CHTS6 mutations were missense mutations, and 25.81% were non-sense mutations. Hot regions were located in exons 4 and 12 of TGFBI individuals and located in exon 3 of CHTS6 individuals. No de novo mutations were identified.ConclusionFor the first time, our large cohort study systematically described the variation spectrum of 22 CD-related genes and evaluated the frequency and pathogenicity of all 2334 distinct high-quality variants in our IED cohort. Our research will provide East Asia and other populations with baseline data from a Han ethnic population-specific level.

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