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
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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
Other Organizer-specific
Transcription Factors from Zygote
Frisbee and Dickkopf-1:
Newly Discovered Wnt Antogonists Secreted by the Organizer 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. |
