BMPs negatively regulate structure and function of the limb apical ectodermal ridge

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 883-894 ◽  
Author(s):  
S. Pizette ◽  
L. Niswander
Keyword(s):  
Sonic Hedgehog ◽  
Posterior Part ◽  
Tissue Growth ◽  
Apical Ectodermal Ridge ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Limb Outgrowth ◽  
Embryonic Limb ◽  
And Function ◽  
Insight Into

The apical ectodermal ridge (AER), a transient specialized epithelium at the distal limb tip, is essential for vertebrate embryonic limb outgrowth along the proximodistal axis. Among all the molecules expressed in the AER, only the Fibroblast Growth Factors (FGFs) have been shown to substitute for its function in limb outgrowth. After specification of the skeletal progenitors is complete, the AER regresses, having fulfilled its function. However, the cellular processes underlying AER regression remain largely unclear, and the molecular ones, totally unknown. Members of the Bone Morphogenetic Protein (BMP) family are expressed in the AER throughout its life and in the mesenchyme. Our studies using misexpression of Noggin, a BMP inhibitor, reveal an unsuspected role for BMPs in the negative regulation of Fgf expression and AER function. We find that BMPs limit limb outgrowth by promoting AER regression, as BMP inhibition results in persistence of the AER, prolonged Fgf expression and excess soft-tissue growth. In addition, the Noggin misexpression studies uncover an earlier role for BMPs in repression of AER function. Noggin overexpression results in extension of the AER anteriorly and loss of AER asymmetry. We show that overall the AER becomes taller, and its anterior half becomes more similar to a normal posterior AER. In addition, Fgf4 transcripts, which are usually restricted to the posterior half of the AER, are now also expressed anteriorly. Moreover, ectopicFgf4 expression is induced independently of Sonic Hedgehog, contrary to current models of Fgf4 regulation in the limb. Our studies also provide insight into the activity of the hypothesized apical ectodermal maintenance factor (AEMF), which is thought to maintain the tall shape of the posterior part of the AER. Our work shows that the AER is negatively regulated by BMP.

Limb deformity proteins: role in mesodermal induction of the apical ectodermal ridge

Development ◽  
1997 ◽  
Vol 124 (1) ◽  
pp. 133-139 ◽  
Author(s):  
J. Kuhlman ◽  
L. Niswander
Keyword(s):  
Sonic Hedgehog ◽  
Limb Development ◽  
Apical Ectodermal Ridge ◽  
Primary Defect ◽  
Limb Deformity ◽  
Normal Morphology ◽  
Fibroblast Growth Factor 8 ◽  
Skeletal Pattern ◽  
Two Phases ◽  
And Function

During early limb development, distal tip ectoderm is induced by the underlying mesenchyme to form the apical ectodermal ridge. Subsequent limb growth and patterning depend on reciprocal signaling between the mesenchyme and ridge. Mice that are homozygous for mutations at the limb deformity (ld) locus do not form a proper ridge and the anteroposterior axis of the limb is shortened. Skeletal analyses reveal shortened limbs that involve loss and fusion of distal bones and digits, defects in both anteroposterior and proximodistal patterning. Using molecular markers and mouse-chick chimeras we examined the ridge-mesenchymal interactions to determine the origin of the ld patterning defects. In the ld ridge, fibroblast growth factor 8 (Fgf8) RNA is decreased and Fgf4 RNA is not detected. In the ld mesenchyme, Sonic hedgehog (Shh), Evx1 and Wnt5a expression is decreased. In chimeras between ld ectoderm and wild-type mesenchyme, a ridge of normal morphology and function is restored, Fgf8 and Shh are expressed normally, Fgf4 is induced and a normal skeletal pattern arises. These results suggest that the ld mesenchyme is unable to induce the formation of a completely functional ridge. This primary defect causes a disruption of ridge function and subsequently leads to the patterning defects observed in ld limbs. We propose a model in which ridge induction requires at least two phases: an early competence phase, which includes induction of Fgf8 expression, and a later differentiation phase in which Fgf4 is induced and a morphological ridge is formed. Ld proteins appear to act during the differentiation phase.

scholarly journals The interplay of the type II TA system with other processes

2019 ◽  
Author(s):  
Wei Wen-ping ◽  
Jia Wan Zhong ◽  
Yang Min
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Environmental Stress ◽  
Regulatory Mechanism ◽  
Phage Infection ◽  
Type Ii ◽  
System Research ◽  
Cellular Processes ◽  
The Stability ◽  
And Function ◽  
Insight Into

The type II toxin antitoxin (TA) system is the most well-studied TA system and is widely distributed in bacteria, especially pathogens such as Mycobacterium tuberculosis. Type II TA system plays an important role in many cellular processes, including maintaining the stability of mobile genetic elements, and bacterial altruistic suicide in response to nutritional starvation, environmental stress and phage infection. Interactions between toxin proteins and antitoxin proteins are critical for the regulation and function of type II TA systems; indeed, the understanding of their function is mainly derived from interaction and regulation of paired TA system proteins. Nonetheless, investigating interaction between unpaired TA system proteins, and the interaction between TA system proteins and other functional proteins, are becoming more common and have provided new insight into the complexity of its regulatory mechanism. In this review, we outlined the cross-interaction between TA system proteins, and the interaction between TA system proteins and other functional proteins, and we are trying to explain novel mechanism of TA system in the regulation of cellular activities. On this basis, we further discussed the knowledge and physiological implications of the relevant aspects of TA system research.

BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4449-4461 ◽  
Author(s):  
Kyung Ahn ◽  
Yuji Mishina ◽  
Mark C. Hanks ◽  
Richard R. Behringer ◽  
E. Bryan Crenshaw
Keyword(s):  
Limb Development ◽  
Apical Ectodermal Ridge ◽  
Bmp Signaling ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Gene Encoding ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Embryonic Limb

We demonstrate that signaling via the bone morphogenetic protein receptor IA (BMPR-IA) is required to establish two of the three cardinal axes of the limb: the proximal-distal axis and the dorsal-ventral axis. We generated a conditional knockout of the gene encoding BMPR-IA (Bmpr) that disrupted BMP signaling in the limb ectoderm. In the most severely affected embryos, this conditional mutation resulted in gross malformations of the limbs with complete agenesis of the hindlimbs. The proximal-distal axis is specified by the apical ectodermal ridge (AER), which forms from limb ectoderm at the distal tip of the embryonic limb bud. Analyses of the expression of molecular markers, such as Fgf8, demonstrate that formation of the AER was disrupted in the Bmpr mutants. Along the dorsal/ventral axis, loss of engrailed 1 (En1) expression in the non-ridge ectoderm of the mutants resulted in a dorsal transformation of the ventral limb structures. The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb. This study demonstrates that BMPR-IA signaling plays a crucial role in AER formation and in the establishment of the dorsal/ventral patterning during limb development.

scholarly journals The interplay of the type II TA system with other processes

2019 ◽  
Author(s):  
Wei Wen-ping ◽  
Jia Wan Zhong ◽  
Yang Min
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Environmental Stress ◽  
Regulatory Mechanism ◽  
Phage Infection ◽  
Type Ii ◽  
System Research ◽  
Cellular Processes ◽  
The Stability ◽  
And Function ◽  
Insight Into

The type II toxin antitoxin (TA) system is the most well-studied TA system and is widely distributed in bacteria, especially pathogens such as Mycobacterium tuberculosis. Type II TA system plays an important role in many cellular processes, including maintaining the stability of mobile genetic elements, and bacterial altruistic suicide in response to nutritional starvation, environmental stress and phage infection. Interactions between toxin proteins and antitoxin proteins are critical for the regulation and function of type II TA systems; indeed, the understanding of their function is mainly derived from interaction and regulation of paired TA system proteins. Nonetheless, investigating interaction between unpaired TA system proteins, and the interaction between TA system proteins and other functional proteins, are becoming more common and have provided new insight into the complexity of its regulatory mechanism. In this review, we outlined the cross-interaction between TA system proteins, and the interaction between TA system proteins and other functional proteins, and we are trying to explain novel mechanism of TA system in the regulation of cellular activities. On this basis, we further discussed the knowledge and physiological implications of the relevant aspects of TA system research.

scholarly journals The interplay of the type II TA system with other processes

2019 ◽  
Author(s):  
Yang Min ◽  
Wei Wen-ping ◽  
Jia Wan Zhong ◽  
He ZhengGuo
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Environmental Stress ◽  
Regulatory Mechanism ◽  
Phage Infection ◽  
Type Ii ◽  
System Research ◽  
Cellular Processes ◽  
The Stability ◽  
And Function ◽  
Insight Into

The type II toxin antitoxin (TA) system is the most well-studied TA system and is widely distributed in bacteria, especially pathogens such as Mycobacterium tuberculosis. Type II TA system plays an important role in many cellular processes, including maintaining the stability of mobile genetic elements, and bacterial altruistic suicide in response to nutritional starvation, environmental stress and phage infection. Interactions between toxin proteins and antitoxin proteins are critical for the regulation and function of type II TA systems; indeed, the understanding of their function is mainly derived from interaction and regulation of paired TA system proteins. Nonetheless, investigating interaction between unpaired TA system proteins, and the interaction between TA system proteins and other functional proteins, are becoming more common and have provided new insight into the complexity of its regulatory mechanism. In this review, we outlined the cross-interaction between TA system proteins, and the interaction between TA system proteins and other functional proteins, and we are trying to explain novel mechanism of TA system in the regulation of cellular activities. On this basis, we further discussed the knowledge and physiological implications of the relevant aspects of TA system research.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

Computational Approaches to Predict the Non-canonical DNAs

2019 ◽  
Vol 14 (6) ◽  
pp. 470-479 ◽  
Author(s):  
Nazia Parveen ◽  
Amen Shamim ◽  
Seunghee Cho ◽  
Kyeong Kyu Kim
Keyword(s):  
Computational Methods ◽  
Genetic Instability ◽  
Computational Prediction ◽  
Structure And Function ◽  
Sequence Motifs ◽  
Computational Approaches ◽  
Functional Roles ◽  
And Function ◽  
Genetic Events ◽  
Insight Into

Background: Although most nucleotides in the genome form canonical double-stranded B-DNA, many repeated sequences transiently present as non-canonical conformations (non-B DNA) such as triplexes, quadruplexes, Z-DNA, cruciforms, and slipped/hairpins. Those noncanonical DNAs (ncDNAs) are not only associated with many genetic events such as replication, transcription, and recombination, but are also related to the genetic instability that results in the predisposition to disease. Due to the crucial roles of ncDNAs in cellular and genetic functions, various computational methods have been implemented to predict sequence motifs that generate ncDNA. Objective: Here, we review strategies for the identification of ncDNA motifs across the whole genome, which is necessary for further understanding and investigation of the structure and function of ncDNAs. Conclusion: There is a great demand for computational prediction of non-canonical DNAs that play key functional roles in gene expression and genome biology. In this study, we review the currently available computational methods for predicting the non-canonical DNAs in the genome. Current studies not only provide an insight into the computational methods for predicting the secondary structures of DNA but also increase our understanding of the roles of non-canonical DNA in the genome.

scholarly journals Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1960
Author(s):  
K. Tanuj Sapra ◽  
Ohad Medalia
Keyword(s):  
Intermediate Filaments ◽  
Eukaryotic Cell ◽  
Coiled Coils ◽  
Cellular Functions ◽  
Mechanical Pressure ◽  
Mechanical Feature ◽  
Cellular Processes ◽  
Nuclear Lamins ◽  
Filament Networks ◽  
And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

scholarly journals Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

2021 ◽  
Author(s):  
Daniel Elieh Ali Komi ◽  
Wolfgang M. Kuebler
Keyword(s):  
State Of The Art ◽  
Extracellular Dna ◽  
Cellular Mechanisms ◽  
Extracellular Traps ◽  
Synthetic Chemicals ◽  
Dna Strands ◽  
Associated Proteins ◽  
Microbial Defense ◽  
And Function ◽  
Insight Into

AbstractMast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense.

scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

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