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

Embryonic Induction during Vertebrate Development: Neural Induction

Do we finally know what Spemann's Organizer substance is?

The developmental significance of the dorsal lip of the blastopore, which is derived from the gray crescent, was initially demonstrated by the organizer transplant experiments conducted by Spemann and Mangold. They demonstrated that dorsal lip material transplanted to the ventral side of a host gastrula would induce a secondary embryo. The transplanted dorsal lips induced the overlying host ectoderm to develop as neural tissue through vertical signaling.

You should review the following aspects of neural induction in your textbook (Browder et al., 1991, pages 485-496; Gilbert, 1997, pages 613-629; Kalthoff, 1996, pages 249-262; Shostak, 1991, pages 583-602); Wolpert et al., 1998, pages 110-122):

  • Spemann-Mangold experiment
  • Regional determination by the chordamesoderm
  • Planar (lateral) vs. vertical signaling

Kessler and Melton (1994; see Fig. 3) have summarized very nicely the interactions that are involved in induction and regionalization of the central nervous system in Xenopus. As shown in Fig. 3, the involuting dorso-anterior mesoderm induces the adjacent mesoderm to form anterior neural tissue. As the mesoderm migrates toward the former animal pole, it contacts progressively more overlying ectoderm, which is also induced to form anterior neural tissue. As involution proceeds, ectoderm is progressively contacted by more posterior mesoderm, which induces more posterior neural elements. According to this model, the anteroposterior character of the neural ectoderm is dependent upon corresponding differences in the underlying dorsal mesoderm.

Inducing Factors

The discovery of neural induction by Spemann triggered a decades-long search for the "inductive factor". The recent discovery of the involvement of growth factor signaling in mesoderm induction has facilitated progress in understanding the molecular and cellular basis for neural induction. Some of the factors implicated in mesoderm induction may also play a role in neural induction.

At this point, three secreted factors have been identified as likely neural inducers. These include noggin, chordin and follistatin. Noggin and chordin were initially identified as secreted factors that can dorsalize the mesoderm. Follistatin is an activin antogonist that can also dorsalize mesoderm when injected as mRNA. Messenger RNA for all three factors can cause induction of neural tissues from the isolated animal cap of Xenopus. Likewise, all three are expressed in the dorsal lip and axial mesoderm of neurulae. Thus, they are expressed in the right time and place to function in neural induction. The neural tissue that they induce has properties of anterior - rather than posterior - neural tissue. For example, Noggin protein can induce anterior and general neural markers (NCAM and XIF3 mRNA; XAG-1 and otx2 [formerly otxA] protein; Figs. 1, 3 and 4, Lamb et al., 1993) in animal pole explants in the absence of detectable mesoderm. Recall that noggin transcripts are synthesized in the organizer at the gastrula stage and in the notochord at later stages; both of these tissues have been implicated in neural induction. Noggin protein, however, had little or no ability to induce posterior neural markers (e.g., ß-tubulin mRNA, En-2, Krox20 and XlHbox6 protein). Thus, Lamb et al. (1993) concluded that noggin can apparently induce anterior neural tissue, but it cannot induce posterior neural tissue. More recently, Knecht et al. (1995) have shown that noggin may also be involved in dorsal-ventral patterning in the forebrain.

What each of these secreted factors (noggin, chordin and follistatin) have in common is that they are inhibitors. They can inhibit the function of bone morphogenetic protein (BMP)-4, which is a TGF-ß family member that has strong mesoderm ventralizing and antineuralizing activity. Likewise, BMP-4 can counteract neural induction by each of these factors in animal caps. Interestingly, when BMP-4 signaling is blocked in animal caps, neural tissue is formed in the absence of neural inducers. BMP-4 is expressed throughout the gastrula of Xenopus, except for the dorsal lip and animal cap regions. Thus, it is expressed at the right time and in the right places to be a ventralizing signal. This evidence suggests that both the mesoderm and ectoderm are patterned by antagonizing signals, with BMP-4 acting to ventralize them. If the effects of BMP-4 are counteracted, the mesoderm develops dorsal properties, and the ectoderm becomes neural tissue. Interestingly, a similar, but inverse, system is responsible for specification of the central nervous system in Drosophila, which suggests that this mechanism has been conserved in evolution. (For a review of Ectodermal Patterning in Vertebrate Embryos, see Sasai and De Robertis, 1997).

The proposed neural inducers (noggin, chordin and follistatin) all promote the formation of anterior neural tissue. Thus, additional factors are required to produce posterior neural ectoderm. Possible factors involved in posteriorization are FGF, retinoic acid and Wnt-3a (Sasai and De Robertis, 1997).

It is obvious that - like the mesoderm - the patterning of the neural ectoderm requires more than a single factor. Spemann's search for the inducing principle has blossomed into a growth industry that has produced a long list of factors that may be involved in induction and patterning. Identification of the actual players and elucidation of their specific roles in induction, however, remain to be resolved. Nevertheless, we are close to knowing in molecular terms how the Xenopus embryo generates a bilaterally symmetric embryo with three germ layers and a central nervous system with anterior-posterior patterning from a radially symmetric egg.


Learning Objectives

  • Review the Spemann-Mangold experiment.
  • Review the classical evidence for regional determination by the chordamesoderm.
  • Review the evidence for planar (lateral) and vertical signaling
  • Review the effects of noggin, chordin and follistatin on both mesoderm and ectoderm.
  • How are these three substances thought to promote neural development?
  • What is BMP-4, and what is its presumed mode of action in ectodermal patterning?
  • Starting with fertilization, trace the sequence of signaling events that culminate in formation of neural tissue.


Digging Deeper:

Links to Related Material

Regionalization of the Mesoderm

Spemann's induction experiments and Mechanism of Organizer Action from Zygote

Regional specificity from Zygote

Recent References

Bang, A.G., Papalopulu, N., Kintner, C. and Goulding, M.D. 1997. Expression of Pax-3 is initiated in the early neural plate by posteriorizing signals produced by the organizer and by posterior non-axial mesoderm. Development 124: 2075-2085.

Filosa, S., Rivera-Pérez, J.A., Gómez, A.P., Gansmuller, A., Sasaki, H., Behringer, R.R. and Ang, S.-L. 1997. goosecoid and HNF-3ß interact to regulate neural tube patterning during mouse embryogenesis. Development 124: 2843-2854.

Foley, A.C., Storey, K.G. and Stern, C.D. 1997. The prechordal region lacks neural inducing activity, but can confer anterior character to more posterior neuroepithelium. Development 124: 2983-2996.

Halpern, M.E., Hatta, K., Amacher, S.L., Talbot, W.S., Yan, Y.-L., Thisse, B., Thisse, C., Postlethwait, J.H. and Kimmel, C.B. 1997. Genetic interactions in zebrafish midline development. Develop. Biol. 187: 154-170.

Lee, J., Platt, K.A., Censullo, P. and Ruiz i Altaba. 1997. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124: 2537-2552.

Poznanski, A. and Keller, R. 1997. The role of planar and early vertical signaling in patterning the expression of Hoxb-1 in Xenopus. Develop. Biol. 184: 351-366.

Saha, M.S., Miles, R.R. and Grainger, R.M. 1997. Dorsal-ventral patterning during neural induction in Xenopus: assessment of spinal cord regionalization with xHB9, a marker for the motor neuron region. Develop. Biol. 187: 209-223.

Sasai, Y. and De Robertis, E.M. 1997. Ectodermal patterning in vertebrate embryos. Develop. Biol. 182: 5-20.

Shimamura, K. and Rubenstein, J.L.R. 1997. Inductive interactions direct early regionalization of the mouse forebrain. Development 124: 2709-2718.

Suzuki, A., Ueno, N. and Hemmati-Brivanlou, A. 1997. Xenopus msx1 mediates epidermal induction and neural inhibition by BMP4. Development. 124: 3037-3044.

Wada, H., Holland, P.W.H., Sato, S., Yamamoto, H. and Satoh, N. 1997. Neural tube is partially dorsalized by overexpression of HrPax-37: the ascidian homologue of Pax-3 and Pax-7. Develop. Biol. 187: 240-252.

Wassarman, K.M., Lewandoski, M., Campbell, K., Joyner, A.L., Rubenstein, J.L.R., Martinez, S. and Martin, G.R. 1997. Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development 124: 2923-2934.

Wilson, P.A., Lagna, G., Suzuki, A. and Hemmati-Brivanlou, A. 1997. Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1. Development 124: 3177-3184.

Woo, K. and Fraser, S.E. 1997. Specification of the zebrafish nervous system by nonaxial signals. Science 277: 254-257.

Wrischnik, L.A. and Kenyon, C.J. 1997. The role of lin-22, a hairy/Enhancer of split homolog, in patterning the peripheral nervous system of C. elegans. Development 124: 2875-2888.


References

Browder, L.W., C.A. Erickson and W.R. Jeffery. 1991. Developmental Biology. Third ed. Saunders College Publishing. Philadelphia.

Gilbert, S.F. 1997. Developmental Biology. Fifth Edition. Sinauer. Sunderland, MA.

Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill. New York.

Kessler, D.S. and D. A. Melton. 1994. Vertebrate embryonic induction: mesodermal and neural patterning. Science 266: 596-604.

Knecht, A.K., Good, P.J., Dawid, I.B. and Harland, R.M. 1995. Dorsal-ventral patterning and differentiation of noggin-induced neural tissue in the absence of mesoderm. Development 121: 1927-1936.

Lamb, T.M., Knecht, A.K., Smith, W.C., Stachel, S.E., Economides, A.N., Stahl, N., Yancopolous, G.D., and Harland, R.M. 1993. Neural induction by the secreted polypeptide noggin. Science 262: 713-718.

Sasai, Y. and De Robertis, E.M. 1997. Ectodermal patterning in vertebrate embryos. Develop. Biol. 182: 5-20.

Shostak, S. 1991. Embryology. HarperCollins. New York

Wolpert, L., Beddington, R., Brockes, J., Jessell, T., Lawrence, P. and Meyerowitz, E. 1998. Principles of Development. Current Biology. London.


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 Wednesday, July 15, 1998