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Zebrafish genetics and vertebrate heart formation

Key Points

  • The zebrafish is an ideal model organism to study the development of vertebrate-specific organs, such as the heart, because it is amenable to both loss-of-function and gain-of-function analyses.

  • Zebrafish embryos are well suited to studies of heart development because, unlike mouse and chick embryos, they do not completely depend on a functional cardiovascular system. Their small size means that they receive sufficient oxygen by passive diffusion to survive even with severe cardiovascular defects. Zebrafish embryos also develop rapidly and are easy to analyse because of their optical clarity.

  • Mutagenesis screens have generated zebrafish mutants that have a range of developmental defects that span the different stages of heart development. These include:

     • Mutants that affect myocardial differentiation, such as swirl, one-eyed pinhead, faust and acerebellar

     • Mutants that affect endocardial differentiation, such as cloche

     • Mutants that affect the migration of myocardial and endocardial precursors, such as hands off, casanova, bonnie and clyde, miles apart and two-of-hearts

     • Mutants that affect the formation of the heart tube, such as heart and soul

     • Mutants that affect the formation of the cardiac chamber, such as one-eyed pinhead, faust, hands off and pandora

  • Analysis of the miles apart mutant has revealed a previously unknown role for the lysosphingolipid receptor, sphingosine 1-phosphate (S1P), in the migration of myocardial cells to the midline. The S1P receptor encoded by miles apart is required cell non-autonomously for this migration, although many questions regarding its role remain.

  • Together with studies in other vertebrate organisms, zebrafish genetics should provide new insights into heart stem-cell differentiation and contribute to novel diagnostic and therapeutic opportunities for human heart disorders.

Abstract

Forward-genetic analyses in Drosophila and Caenorhabditis elegans have given us unprecedented insights into many developmental mechanisms. To study the formation of organs that contain cell types and structures not present in invertebrates, a vertebrate model system amenable to forward genetics would be very useful. Recent work shows that a newly initiated genetic approach in zebrafish is already making significant contributions to understanding the development of the vertebrate heart, an organ that contains several vertebrate-specific features. These and other studies point to the utility of the zebrafish system for studying a wide range of vertebrate-specific processes.

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Figure 1: Zebrafish heart development.
Figure 2: Cardia bifida.
Figure 3: Cardiac valve formation.

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Acknowledgements

Past and present members of the lab contributed substantially to the ideas and work summarized here. D. Yelon, E. Walsh, S. Horne, A. Chin, N. Osborne and T. Bartman provided helpful comments on the manuscript. Work in the lab is supported by grants from the NIH and AHA, as well as the Packard, Sandler and Mabel Gee foundations.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASE LINKS

MyoD

Myogenin

Myf5

tinman

Nk2 family

nkx2.5

DPP

Bmp2

swr

fau

ace

Bmp2b

Oep

Gata5

Fgf8

Gata4

Gata5

Gata6

Vegfr2

hhex

scl

grl

fibronectin

han

cas

bon

mil

nat

hand2

wunen

slb

Wnt11

troponin T

tropomyosin

myosin

mef2

tbx5

hrt

pandora

tricuspid atresia

pulmonic stenosis

aortic stenosis

versican

vinculin

FURTHER INFORMATION

Fishscope

Tübingen zebrafish stock centre

ZFIN

Didier Stainier's lab

Zebrafish webserver at Massachusetts General Hospital

Trans-NIH zebrafish initiative

Tübingen map of the zebrafish genome

ENCYCLOPEDIA OF LIFE SCIENCES

Zebrafish embryo as a developmental system

Glossary

ANDROGENESIS

Development of an embryo from a fertililized egg, when the embryo's entire genetic material comes from the sperm.

GYNOGENESIS

Development of an embryo from a fertilized egg, when the embryo's entire genetic material comes from the egg.

SMAD

Transcriptional effector of transforming growth factor β (TGFβ) signalling. Upon phosphorylation by TGFβ receptors, Smads form a transcriptional complex that enters the nucleus. Different Smads are phosphorylated in response to different TGFβ ligands and directly regulate the expression of target genes.

NODAL

A ligand of the transforming growth factor β family that signals through the Smad signal-transduction pathway.

CELL AUTONOMOUS

A genetic trait in which only genotypically mutant cells show the mutant phenotype.

HYPOMORPHIC MUTATION

A mutation that does not completely eliminate the wild-type function of a gene and therefore causes a less severe phenotype than a loss-of-function (or null) mutation.

AORTIC BIFURCATION

The process whereby the paired lateral dorsal aortae fuse into a single medial aorta in the anterior trunk region.

MESP1

Mesp1 encodes a basic helix–loop–helix (bHLH) transcription factor and is expressed in the migrating myocardial cells of the mouse.

LYSOSPHINGOLIPIDS

Also called lysophospholipids, these lipids belong to the sphingolipid class and are partly generated by the enzymatic cleavage of membrane lipids. They include molecules such as lysophosphatidic acid and sphingosine 1-phosphate.

CELL NON-AUTONOMOUS

A cell non-autonomous trait is one in which genotypically mutant cells cause other cells (regardless of their genotype) to show a mutant phenotype.

DOMINANT INTERFERENCE

Technique by which, in this case, a transcriptional activator was changed to a repressor through the generation of a chimeric protein.

LEADER SEQUENCE

The non-translated sequence at the 5′ end of mRNA that precedes the initiation codon.

CARDIAC JELLY

The wide extracellular matrix between the myocardium and endocardium.

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Stainier, D. Zebrafish genetics and vertebrate heart formation. Nat Rev Genet 2, 39–48 (2001). https://doi.org/10.1038/35047564

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