Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart ...regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction ofgata4regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation ofgata4regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying ...repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature.
In the embryo, the neural crest is an important population of cells that gives rise to diverse derivatives, including the peripheral nervous system and the craniofacial skeleton. Evolutionarily, the ...neural crest is of interest as an important innovation in vertebrates. Experimentally, it represents an excellent system for studying fundamental developmental processes, such as tissue induction. Classical embryologists have identified interactions between tissues that lead to neural crest formation. More recently, geneticists and molecular biologists have identified the genes that are involved in these interactions; this recent work has revealed that induction of the neural crest is a complex multistep process that involves many genes.
The distribution of effect sizes of genes underlying adaptation is unknown (Orr 2005). Are suites of traits that diverged under natural selection controlled by a few pleiotropic genes of large effect ...(major genes model), by many independently acting genes of small effect (infinitesimal model), or by a combination, with frequency inversely related to effect size (geometric model)? To address this we carried out a quantitative trait loci (QTL) study of a suite of 54 position traits describing body shapes of two threespine stickleback species: an ancestral Pacific marine form and a highly derived benthic species inhabiting a geologically young lake. About half of the 26 detected QTL affected just one coordinate and had small net effects, but several genomic regions affected multiple aspects of shape and had large net effects. The distribution of effect sizes followed the gamma distribution, as predicted by the geometric model of adaptation when detection limits are taken into account. The sex-determining chromosome region had the largest effect of any QTL. Ancestral sexual dimorphism was similar to the direction of divergence, and was largely eliminated during freshwater adaptation, suggesting that sex differences may provide variation upon which selection can act. Several shape QTL are linked to Eda, a major gene responsible for reduction of lateral body armor in freshwater. Our results are consistent with predictions of the geometric model of adaptation. Shape evolution in stickleback results from a few genes with large and possibly widespread effects and multiple genes of smaller effect.
The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly
. Improved methods ...include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain.
Summary
Cellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the ...senescence‐associated secretory phenotype (SASP). The senescence biomarker p16INK4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16INK4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16INK4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16INK4a in murine and human models of chondrocyte aging. We observed that p16INK4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16INK4a expression. Moreover, increased chondrocyte p16INK4a expression correlated with several SASP transcripts. Despite the relationship between p16INK4a expression and these features of senescence, somatic inactivation of p16INK4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16INK4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.
Cellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the senescence‐associated ...secretory phenotype (
SASP
). The senescence biomarker
p16
INK
4a
is a potent inhibitor of the cell cycle but is not essential for
SASP
production. Thus, it is unclear whether
p16
INK
4a
identifies senescence in hyporeplicative cells such as articular chondrocytes and whether
p16
INK
4a
contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of
p16
INK
4a
in murine and human models of chondrocyte aging. We observed that
p16
INK
4a
mRNA
expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (
r
2
= .27,
p
< .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (
CDK
4/6), and proliferation was reduced in cells from older donors with increased
p16
INK
4a
expression. Moreover, increased chondrocyte
p16
INK
4a
expression correlated with several
SASP
transcripts. Despite the relationship between
p16
INK
4a
expression and these features of senescence, somatic inactivation of
p16
INK
4a
in chondrocytes of adult mice did not mitigate
SASP
expression and did not alter the rate of osteoarthritis (
OA
) with physiological aging or after destabilization of the medial meniscus. These results establish that
p16
INK
4a
expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on
OA
are more likely driven by production of
SASP
molecules than by loss of chondrocyte replicative function.
Cellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro-inflammatory molecules known as the senescence-associated ...secretory phenotype (SASP). The senescence biomarker p16
is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16
identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16
contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16
in murine and human models of chondrocyte aging. We observed that p16
mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50-fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r
= .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin-dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16
expression. Moreover, increased chondrocyte p16
expression correlated with several SASP transcripts. Despite the relationship between p16
expression and these features of senescence, somatic inactivation of p16
in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16
expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.
Neural Induction by the Secreted Polypeptide Noggin Lamb, Teresa M.; Knecht, Anne K.; Smith, William C. ...
Science (American Association for the Advancement of Science),
10/1993, Letnik:
262, Številka:
5134
Journal Article
Recenzirano
The Spemann organizer induces neural tissue from dorsal ectoderm and dorsalizes lateral and ventral mesoderm in Xenopus. The secreted factor noggin, which is expressed in the organizer, can mimic the ...dorsalizing signal of the organizer. Data are presented showing that noggin directly induces neural tissue, that it induces neural tissue in the absence of dorsal mesoderm, and that it acts at the appropriate stage to be an endogenous neural inducing signal. Noggin induces cement glands and anterior brain markers, but not hindbrain or spinal cord markers. Thus, noggin has the expression pattern and activity expected of an endogenous neural inducer.
A dorsalizing signal acts during gastrulation to change the specification of lateral mesodermal tissues from ventral (blood, mesenchyme) to more dorsal fates (muscle, heart, pronephros). This signal, ...from Spemann's organizer, cannot be mimicked by the mesoderm inducers activin and fibroblast growth factor. The gene noggin is expressed in the organizer, and could be the dorsalizing signal. Here we show that soluble noggin protein added to ventral marginal zones during gastrulation induces muscle, but that activin does not. Dorsal pattern can be partially rescued in ventralized embryos by injection of a plasmid that expresses noggin during gastrulation. The results suggest that the noggin product may be the dorsalizing signal from the organizer.
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