Dynamic Development

CONTENTS

Main Page Dynamic Development

The Foundations of Developmental Biology

Gametogenesis

From Sperm and Egg to Embryo

Genetic Regulation of Development

Organizing the Multicellular Embryo

Generating Cell Diversity


Dynamic Development at a Glance


Learning Resources

Research Resources

The Developmental Biology Journal Club

Developmental Biology Tutorial

Left-right Asymmetry

OK, so symmetry isn't perfect.

At first glance, the left and right sides of our bodies are identical to one-another. However, internally, some of our visceral organs are displaced to one side. The heart, for example, loops to the right side. This looping is consistent in the vertebrates and occurs very early in development. Rare individuals have the opposite symmetry, which is known as situs inversus.

How is left-right asymmetry (often referred to as handedness) established during development? One way to begin studying this problem is to search for genes that are expressed early in development only on one side of the embryo and to formulate hypotheses on the origin and manifestation of handedness. Then experiments can be conducted to test these hypotheses.

In fact, a number of asymmetrically-expressed genes have been discovered, and we are on our way toward understanding how handedness develops. The first gene that was discovered to have asymmetrical expression is Sonic hedgehog, which is expressed on the left side of the gastrulating chick embryo. A screen of the expression patterns of developmentally significant genes in early chick embryos has revealed asymmetric patterns of mRNA expression for transcripts encoding a number of important signaling molecules (Table. 1, Fig. 1).

Table 1
Asymmetric Gene Expression in the Gastrulating Chick Embryo
(After Levin, 1997)

 Gene

Side of Expression 

Activin ßB
(TGF-ß  family member)
Right 
 cAct-RIIa
(activin receptor)
Right
Sonic hedgehog (Shh)
(signaling molecule) 
Left
 HNF3-ß
(Winged-helix transcription factor)
Left 
nodal 
TGF-ß family signaling molecule
Left
cWnt-8C
(wnt-family member signaling molecule) 
Right 
PTC
(receptor molecule) 
 Left
follistatin
(signaling molecule) 
Right 

The demonstration of asymmetrical patterns of expression of these genes has made it possible to investigate the relationships among them so that regulatory interactions among them could be determined. The approaches used have included misexpression of the earlier-expressed genes on the opposite side to determine whether the expression of the later genes would change. In this way, a hierarchical pathway has been established (Fig. 2).

Initially, Shh is expressed throughout Hensen's node. (Hensen's node is a thickening at the anterior end of the primitive streak where presumptive notochord cells accumulate. It is functionally equivalent to the dorsal lip of the blastopore in amphibian embryos.) Somewhat later, activin -ßB is expressed on the right side of Hensen's node. As a consequence, cAct-RIIa is induced on the right side, shutting off expression of Shh on that side. As a consequence, Shh expression becomes limited to the left side of the node and in the notochord. These relationships were established by implanting activin-coated beads in the left side, which induced expression of cAct-RIIa and shut off expression of Shh. Likewise, applying beads coated with the activin inhibitor follistatin on the right side resulted in bilateral Shh expression, suggesting that the Shh asymmetry results from activin activity (Levin, 1997).

Asymmetric Shh expression induces a small domain of cells adjacent to the left side of the node to express nodal. A larger domain of nodal expression follows in the left lateral plate mesoderm. The role of Shh in inducing nodal expression was shown by applying ectopic Shh to the right side, which induces nodal in the right lateral plate mesoderm. Also, endogenous left-side Shh was removed by applying activin to the left side, which suppressed nodal expression (Levin, 1997).

What effects do the misexpression of these genes have on morphology? Misexpression of activin (which eliminates nodal expression), or Shh (which bilateralizes nodal expression) randomize heart looping (Levin et al., 1995). The cardiac precursor cells are in direct contact with the territory of nodal expression. Hence, it is possible that the asymmetric nodal signal causes the cardiac primordia on one side to initiate heart looping. This possibility is supported by the observation that administration of nodal can cause either a reversal of heart looping or symmetric hearts (Levin, 1997).


Figure 1. Genes with left-right asymmetric expression patterns in the chick. (A), cNot is symmetrically expressed around Hensen's node. (B), cAct-RIIa is expressed in the right side of the node. (C), Shh is expressed in the left side of Hensen's node. (D), HNF3-ß is expressed throughout the whole node but has a tail of expression in the left primitive ridge. (E) nodal is expressed in two domains, in the endoderm next to the left side of the node (red arrow), and the left lateral plate mesoderm. cWnt-8C (F), and PTC (G) are also asymmetrically expressed in the gastrulating chick embryo. White arrows, no expression; black arrows, expression domain. (From Levin, 1997. Reproduced from BioEssays with permission of The Company of Biologists.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2. A LR pathway. (A), Diagram of asymmetrically expressed genes in a gastrulating chick embryo. (B), Diagram of the regulatory interactions between known members of the LR pathway. (From Levin, 1997. Reproduced from BioEssays with permission of The Company of Biologists.)


Learning Objectives

  • Review the spatio-temporal patterns of expression of the genes discussed in this module.
  • Describe the experiments that have demonstrated the cascade of events that may be involved in asymmetrical heart looping. Derive conclusions from each experiment.


Digging Deeper:

Recent Literature

Lohr, J.L., Danos, M.C. and Yost, H.J. 1997. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124: 1465-1472.

Links to Related Material

Left-right Asymmetry in Vertebrates: Report by Isaac et al. and Science Perspective by Robertson.


References

Levin, M. 1997. Left-right asymmetry in vertebrate embryogenesis. BioEssays 19: 287-296.

Levin, M., Johnson, R., Stern, C., Kuehn, M. and Tabin, C. 1995. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82: 1-20.

Riddle, R.D., Johnson, R.L., Laufer, E. and Tabin, C. 1993. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401-1416.


Dynamic Development at a Glance
Main Page Dynamic Development

Dynamic Development is a Virtual Embryo learning resource

This material may be reproduced for educational purposes only provided credit is given to the original source.
Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Thursday, June 25, 1998