scholarly journals A hypomorphic cystathionine ß-synthase gene contributes to cavefish eye loss by disrupting optic vasculature

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Li Ma ◽  
Aniket V. Gore ◽  
Daniel Castranova ◽  
Janet Shi ◽  
Mandy Ng ◽  
...  
Keyword(s):  
Circulatory System ◽  
Astyanax Mexicanus ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
Surface Dwelling ◽  
Blind Cave ◽  
Vestigial Structures ◽  
Key Indicators ◽  
Evolutionary Descent ◽  
Eye Formation

Abstract Vestigial structures are key indicators of evolutionary descent, but the mechanisms underlying their development are poorly understood. This study examines vestigial eye formation in the teleost Astyanax mexicanus, which consists of a sighted surface-dwelling morph and multiple populations of blind cave morphs. Cavefish embryos initially develop eyes, but they subsequently degenerate and become vestigial structures embedded in the head. The mutated genes involved in cavefish vestigial eye formation have not been characterized. Here we identify cystathionine ß-synthase a (cbsa), which encodes the key enzyme of the transsulfuration pathway, as one of the mutated genes responsible for eye degeneration in multiple cavefish populations. The inactivation of cbsa affects eye development by increasing the transsulfuration intermediate homocysteine and inducing defects in optic vasculature, which result in aneurysms and eye hemorrhages. Our findings suggest that localized modifications in the circulatory system may have contributed to the evolution of vestigial eyes in cavefish.

scholarly journals A Hypomorphic Cystathionine ß-Synthase Gene Contributes to Cavefish Eye Loss by Disrupting Optic Vasculature

2019 ◽  
Author(s):  
Li Ma ◽  
Aniket V. Gore ◽  
Daniel Castranova ◽  
Janet Shi ◽  
Mandy Ng ◽  
...  
Keyword(s):  
Oxygen Deficiency ◽  
Circulatory System ◽  
Astyanax Mexicanus ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
Surface Dwelling ◽  
Blind Cave ◽  
Different Populations ◽  
Key Indicators ◽  
Blind Cavefish

AbstractVestigial structures are key indicators of evolutionary descent but the mechanisms underlying their development are poorly understood. This study examines vestigial eye formation in the teleost Astyanax mexicanus, which consists of a sighted surface-dwelling morph and different populations of blind cave morphs. Cavefish embryos initially develop optic primordia but vestigial eyes are formed during larval development. Multiple genetic factors are involved in cavefish eye loss but none of the mutated genes have been identified. Here we identify cystathionine ß-synthase (cbsa), which encodes the key enzyme of the transsulfuration pathway, as a mutated gene responsible for eye degeneration in multiple cavefish populations. The inactivation of cbsa affects eye development by inducing accumulation of the transsulfuration intermediate homocysteine and defects in optic vasculature, including aneurysms and eye hemorrhages, leading to oxygen deficiency. Our findings suggest that localized modifications in the circulatory system and hypoxia had important roles in the evolution of vestigial eyes in blind cavefish.

Regressive Evolution of Pigmentation in the Cavefish Astyanax

2006 ◽  
Vol 52 (3-4) ◽  
pp. 405-422 ◽  
Author(s):  
William R. Jeffery
Keyword(s):  
Neural Crest ◽  
Single Gene ◽  
Pigment Cells ◽  
Loss Of Function ◽  
Coding Region ◽  
Protein Coding ◽  
Regressive Evolution ◽  
Astyanax Mexicanus ◽  
Key Enzyme ◽  
Surface Dwelling

Many cave animals are colorless due to loss of pigment cells. Here, we review recent progress on how and why pigmentation has disappeared in Astyanax mexicanus, a single teleost species with conspecific surface-dwelling (surface fish) and many different cave-dwelling (cavefish) forms. During surface fish development, migratory neural crest cells form three types of pigment cells: silver iridophores, orange xanthophores, and black melanophores. Cavefish have eliminated or substantially reduced their complement of melanophores and exhibit albinism, loss of the capacity to synthesize melanin. Cell tracing, immunolocalization, and neural tube explant cultures show that cavefish have retained a colorless pre-melanophore (melanoblast) lineage derived from the neural crest. Thus, the cavefish neural crest produces melanoblasts that migrate normally but are blocked in differentiation and show defective melanogenesis. Cavefish melanoblasts can convert exogenous L-DOPA into melanin and therefore have active tyrosinase, the key enzyme in melanogenesis. In contrast, cavefish melanoblasts are unable to convert L-tyrosine to L-DOPA (and melanin), although this reaction is also catalyzed by tyrosinase. Thus, cavefish are tyrosinase-positive albinos that have a deficiency in L-tyrosine transport or utilization within the melanosome, the organelle in which melanin is synthesized. At least five different types of Astyanax cavefish show the same defect in melanogenesis. Genetic analysis shows that cavefish albinism is caused by loss of function mutations in a single gene, p/oca2, which encodes a large protein that probably spans the melanosome membrane. Different deletions in the p/oca2 protein-coding region are responsible for loss of function in at least two different cavefish populations, suggesting that albinism evolved by convergence. Based on current understanding of the genetic basis of albinism, we discuss potential mechanisms for regressive evolution of cavefish pigmentation.

scholarly journals In Helicobacter pylori, LuxS Is a Key Enzyme in Cysteine Provision through a Reverse Transsulfuration Pathway

2010 ◽  
Vol 192 (5) ◽  
pp. 1184-1192 ◽  
Author(s):  
Neil C. Doherty ◽  
Feifei Shen ◽  
Nigel M. Halliday ◽  
David A. Barrett ◽  
Kim R. Hardie ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Wild Type ◽  
Metabolic Role ◽  
Absolute Requirement ◽  
Transsulfuration Pathway ◽  
Cysteine Synthesis ◽  
Key Enzyme ◽  
H Pylori ◽  
Isogenic Strains

ABSTRACT In many bacteria, LuxS functions as a quorum-sensing molecule synthase. However, it also has a second, more central metabolic function in the activated methyl cycle (AMC), which generates the S-adenosylmethionine required by methyltransferases and recycles the product via methionine. Helicobacter pylori lacks an enzyme catalyzing homocysteine-to-methionine conversion, rendering the AMC incomplete and thus making any metabolic role of H. pylori LuxS (LuxSHp) unclear. Interestingly, luxS Hp is located next to genes annotated as cysK Hp and metB Hp, involved in other bacteria in cysteine and methionine metabolism. We showed that isogenic strains carrying mutations in luxS Hp, cysK Hp, and metB Hp could not grow without added cysteine (whereas the wild type could), suggesting roles in cysteine synthesis. Growth of the ΔluxS Hp mutant was restored by homocysteine or cystathionine and growth of the ΔcysK Hp mutant by cystathionine only. The ΔmetB Hp mutant had an absolute requirement for cysteine. Metabolite analyses showed that S-ribosylhomocysteine accumulated in the ΔluxS Hp mutant, homocysteine in the ΔcysK Hp mutant, and cystathionine in the ΔmetB Hp mutant. This suggests that S-ribosylhomocysteine is converted by LuxSHp to homocysteine (as in the classic AMC) and thence by CysKHp to cystathionine and by MetBHp to cysteine. In silico analysis suggested that cysK-metB-luxS were acquired by H. pylori from a Gram-positive source. We conclude that cysK-metB-luxS encode the capacity to generate cysteine from products of the incomplete AMC of H. pylori in a process of reverse transsulfuration. We recommend that the misnamed genes cysK Hp and metB Hp be renamed mccA (methionine-to-cysteine-conversion gene A) and mccB, respectively.

scholarly journals An Integrated Transcriptome-Wide Analysis of Cave and Surface Dwelling Astyanax mexicanus

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e55659 ◽  
Author(s):  
Joshua B. Gross ◽  
Allison Furterer ◽  
Brian M. Carlson ◽  
Bethany A. Stahl
Keyword(s):  
Astyanax Mexicanus ◽  
Surface Dwelling

scholarly journals A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionineβ-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
João B. Vicente ◽  
Henrique G. Colaço ◽  
Francesca Malagrinò ◽  
Paulo E. Santo ◽  
André Gutierres ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Redox Homeostasis ◽  
Crystallographic Structure ◽  
Wild Type ◽  
Gene Encoding ◽  
Cellular Redox ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
A Minor ◽  
Ferrous Heme

The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5′-phosphate- (PLP-) dependent cystathionineβ-synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (H2S). CBS activity, contributing to cellular redox homeostasis, is positively regulated byS-adenosyl-L-methionine (AdoMet) but fully inhibited upon CO or NO• binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenicCBSmutations is not yet fully understood. Here we found that the ferrous heme of the reportedly mild p.P49L CBS variant has altered spectral properties and markedly increased affinity for CO, making the protein much more prone than wild type (WT) CBS to inactivation at physiological CO levels. The higher CO affinity could result from the slightly higher flexibility in the heme surroundings revealed by solving at 2.80-Å resolution the crystallographic structure of a truncated p.P49L. Additionally, we report that p.P49L displays impaired H2S-generating activity, fully rescued by PLP supplementation along the purification, despite a minor responsiveness to AdoMet. Altogether, the results highlight how increased propensity to CO inactivation of an otherwise WT-like variant may represent a novel pathogenic mechanism in classical homocystinuria.

scholarly journals Behavioural, physiological and metabolic responses to long-term starvation and refeeding in a blind cave-dwelling (Proteus anguinus) and a surface-dwelling (Euproctus asper) salamander

2001 ◽  
Vol 204 (2) ◽  
pp. 269-281 ◽  
Author(s):  
F. Hervant ◽  
J. Mathieu ◽  
J. Durand
Keyword(s):  
Food Deprivation ◽  
Metabolic Response ◽  
Energy System ◽  
Energy Reserves ◽  
Energy Strategy ◽  
Quick Recovery ◽  
Proteus Anguinus ◽  
Surface Dwelling ◽  
Blind Cave

The effects of long-term starvation and subsequent refeeding on haematological variables, behaviour, rates of oxygen consumption and intermediary and energy metabolism were studied in morphologically similar surface- and cave-dwelling salamanders. To provide a hypothetical general model representing the responses of amphibians to food stress, a sequential energy strategy has been proposed, suggesting that four successive phases (termed stress, transition, adaptation and recovery) can be distinguished. The metabolic response to prolonged food deprivation was monophasic in the epigean Euproctus asper (Salamandridae), showing an immediate, linear and large decrease in all the energy reserves. In contrast, the hypogean Proteus anguinus (Proteidae) displayed successive periods of glucidic, lipidic and finally lipido-proteic-dominant catabolism during the course of food deprivation. The remarkable resistance to long-term fasting and the very quick recovery from nutritional stress of this cave organism may be explained partly by its ability to remain in an extremely prolonged state of protein sparing and temporary torpor. Proteus anguinus had reduced metabolic and activity rates (considerably lower than those of most surface-dwelling amphibians). These results are interpreted as adaptations to a subterranean existence in which poor and discontinuous food supplies and/or intermittent hypoxia may occur for long periods. Therefore, P. anguinus appears to be a good example of a low-energy-system vertebrate.

scholarly journals An epigenetic mechanism for cavefish eye degeneration

2017 ◽  
Author(s):  
Aniket V. Gore ◽  
Kelly A. Tomins ◽  
James Iben ◽  
Li Ma ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Eye Development ◽  
Phenotypic Diversity ◽  
Phenotypic Variability ◽  
Epigenetic Mechanism ◽  
Gene Repression ◽  
Specific Gene ◽  
Astyanax Mexicanus ◽  
Eye Disorders ◽  
Blind Cave

Coding and non-coding mutations in DNA contribute significantly to phenotypic variability during evolution. However, less is known about the role of epigenetics in this process. Although previous studies have identified eye development genes associated with the loss of eyes phenotype in the Pachón blind cave morph of the Mexican tetra Astyanax mexicanus1-6, no inactivating mutations have been found in any of these genes2,3,7-10. Here we show that excess DNA methylation-based epigenetic silencing promotes eye degeneration in blind cave Astyanax mexicanus. By performing parallel analyses in Astyanax mexicanus cave and surface morphs and in the zebrafish Danio rerio, we have discovered that DNA methylation mediates eye-specific gene repression and globally regulates early eye development. The most significantly hypermethylated and down-regulated genes in the cave morph are also linked to human eye disorders, suggesting the function of these genes is conserved across the vertebrates. Our results show that changes in DNA methylation-based gene repression can serve as an important molecular mechanism generating phenotypic diversity during development and evolution.

scholarly journals Genetic analysis reveals candidate genes for activity QTL in the blind Mexican tetra,Astyanax mexicanus

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5189 ◽  
Author(s):  
Brian M. Carlson ◽  
Ian B. Klingler ◽  
Bradley J. Meyer ◽  
Joshua B. Gross
Keyword(s):  
Candidate Genes ◽  
Genetic Basis ◽  
Activity Patterns ◽  
Potential Candidate ◽  
Behavioral Phenotypes ◽  
Astyanax Mexicanus ◽  
Broad Array ◽  
Patterns Of Behavior ◽  
Surface Dwelling

Animal models provide useful tools for exploring the genetic basis of morphological, physiological and behavioral phenotypes. Cave-adapted species are particularly powerful models for a broad array of phenotypic changes with evolutionary, developmental and clinical relevance. Here, we explored the genetic underpinnings of previously characterized differences in locomotor activity patterns between the surface-dwelling and Pachón cave-dwelling populations ofAstyanax mexicanus.We identified multiple novel QTL underlying patterns in overall levels of activity (velocity), as well as spatial tank use (time spent near the top or bottom of the tank). Further, we demonstrated that different regions of the genome mediate distinct patterns in velocity and tank usage. We interrogated eight genomic intervals underlying these activity QTL distributed across six linkage groups. In addition, we employed transcriptomic data and draft genomic resources to generate and evaluate a list of 36 potential candidate genes. Interestingly, our data support the candidacy of a number of genes, but do not suggest that differences in the patterns of behavior observed here are the result of alterations to certain candidate genes described in other species (e.g., teleost multiple tissue opsins, melanopsins or members of the core circadian clockwork). This study expands our knowledge of the genetic architecture underlying activity differences in surface and cavefish. Future studies will help define the role of specific genes in shaping complex behavioral phenotypes inAstyanaxand other vertebrate taxa.

scholarly journals Cavefish cope with environmental hypoxia by developing more erythrocytes and overexpression of hypoxia inducible genes

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Corine M van der Weele ◽  
William R Jeffery
Keyword(s):  
Normal Development ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Astyanax Mexicanus ◽  
Hypoxia Inducible Factor 1 ◽  
Primitive Hematopoiesis ◽  
Cave Environment ◽  
Surface Dwelling ◽  
Inducible Genes ◽  
Lateral Mesoderm

Dark caves lacking primary productivity can expose subterranean animals to hypoxia. We used the surface-dwelling (surface fish) and cave-dwelling (cavefish) morphs of Astyanax mexicanus as a model for understanding the mechanisms of hypoxia tolerance in the cave environment. Primitive hematopoiesis, which is restricted to the posterior lateral mesoderm in other teleosts, also occurs in the anterior lateral mesoderm in Astyanax, potentially pre-adapting surface fish for hypoxic cave colonization. Cavefish have enlarged both hematopoietic domains and develop more erythrocytes than surface fish, which are required for normal development in both morphs. Laboratory induced hypoxia suppresses growth in surface fish but not in cavefish. Both morphs respond to hypoxia by overexpressing hypoxia-inducible factor 1 (hif1) pathway genes, and some hif1 genes are constitutively upregulated in normoxic cavefish to similar levels as in hypoxic surface fish. We conclude that cavefish cope with hypoxia by increasing erythrocyte development and constitutive hif1 gene overexpression.

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