Dorsal lip

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The dorsal lip of the blastopore is a structure that forms during early embryonic development and is important for its role in organizing the germ layers. [1] The dorsal lip is formed during early gastrulation as folding of tissue along the involuting marginal zone of the blastocoel forms an opening known as the blastopore. [2] It is particularly important for its role in neural induction through the default model, where signaling from the dorsal lip protects a region of the epiblast from becoming epidermis, thus allowing it to develop to its default neural tissue. [3]

Contents

Figure 1: Mangold's dorsal lip transplant experiment in Xenopus demonstrated that a transplanted dorsal lip could induce the formation of a double axis in the new host embryo, solidifying the dorsal lip's sufficiency in neural induction (A). Injection of extracted mRNA from the dorsal lip into irradiated Xenopus embryos rescued neural induction and overall development demonstrating there is a genetic basis of neural induction (B). Establishment of cDNA libraries from extracted dorsal lip mRNA identified candidate genes that may be responsible for neural induction. One such candidate gene, noggin, is sufficient for rescuing development of irradiated embryos when its mRNA is injected (C). Experimental evidence of the dorsal lip as the neural inducer and genetic mechanisms..jpg
Figure 1:  Mangold's dorsal lip transplant experiment in Xenopus demonstrated that a transplanted dorsal lip could induce the formation of a double axis in the new host embryo, solidifying the dorsal lip's sufficiency in neural induction (A).  Injection of extracted mRNA from the dorsal lip into irradiated Xenopus embryos rescued neural induction and overall development demonstrating there is a genetic basis of neural induction (B).  Establishment of cDNA libraries from extracted dorsal lip mRNA identified candidate genes that may be responsible for neural induction.  One such candidate gene, noggin, is sufficient for rescuing development of irradiated embryos when its mRNA is injected (C).

Discovery

The dorsal lip refers to the section of tissue located at the site of the first invagination in the developing pregastula and is understood to act as both the neural inducer in the early embryo as well as the overall organizer of the entire body axis. [1]   Early transplantation experiments in developing embryos demonstrated that different layers of the embryo, when isolated and transplanted before gastrulation versus after gastrulation, would develop into distinctly different mature tissues. Dr. Hans Spemann noted this phenomenon and hypothesized that the tissue rearrangements that occurred during gastrulation must somehow be linked to controlling the fates of developing tissue in the embryo. [4]   His research focused on the dorsal lip as a possible organizer of these fate specification changes since it is the first structure to fold inwards during gastrulation. Transplantation of the dorsal lip from a Xenopus embryo into the ventral region of a different host embryo demonstrated that an entire secondary axis would form using the host embryo's own tissue, indicating a clear role of the dorsal lip as a neural inducer and organizer. [5]   The dorsal lip of the developing gastrula was thus denoted as the Spemann-Mangold organizer for its role in neural induction and organization of developing neural tissues.

Interest then shifted to identifying the chemical mechanisms underlying the dorsal lip's organizer function.  Future experiments using a series of injections of dorsal lip mRNA into irradiated embryos demonstrated that the dorsal lip contained genetic factors that were sufficient for neural induction.  Further investigations were able to identify specific factors such as noggin and chordin as genetic factors in the dorsal lip that are critical for proper neural development. [6]

Genetic information for neural induction

Experiments to identify the genetic basis for neural induction were conducted by exposing Xenopus embryos to UV radiation, which causes them to develop with no head. [7] Dr. Richard Harland and Dr. William Smith extracted mRNA from the dorsal lip of normally developing Xenopus embryos that was then injected into the UV-radiated embryos to see if normal head development could be rescued. [2] [7] These experiments determined that noggin mRNA can induce normal head and brain development, and that increasing levels of noggin result in larger brain structures and eventually a secondary axis. [8]

Similar experiments in the lab of Dr. Edward DeRobertis identified that chordin cDNA could also induce a secondary axis, suggesting that there is redundancy in the genes that code for neural development. [9] To test whether only one or both genes are required for neural induction, genetically modified knockout mice were used. Mice that had either the noggin gene or the chordin gene deleted developed without some head structures such as ears, but had generally intact development. [10] Mice that had a double knockout of both noggin and chordin, however, developed with no brain, demonstrating that there are multiple genes contributing to similar functions of neural development. [10]

A different set of studies identified yet another molecule, follistatin, that is involved in neural induction. This was a result of the work of Doug Melton and Ali Hemmati-Brivanlou, who were studying the function of activin, a signalling molecule that acts on TGF-β receptors. [5] They discovered that by mutating the activin receptor, tissue that would normally develop into epidermis instead becomes neural tissue. [11] This gave insight into the signalling mechanism of neural induction, as it was shown that inhibiting TGF-β receptors leads to the formation of neural tissue. [12] [13] Follistatin was identified as a TGF-β inhibitor, and it was later shown that chordin and noggin both work alongside follistatin to inhibit bone morphogenic proteins (BMPs) from activating TGF-β. [6] Through this signalling mechanism, the dorsal lip of the blastopore protects tissue from becoming epidermis, allowing the default formation of neural tissue [3]

Formation of the dorsal lip

Before the structural formation of the dorsal lip occurs another signaling center known as the Nieuwkoop center, located in the vegetal region of the developing blastocoel, is responsible for organizing the polarity patterns needed to form the dorsal lip. The Nieuwkoop center was discovered to be responsible for dorso-ventral polarity establishment through Wnt/GSK/beta-catenin. [14]  This dorsalizing signal allows for the Spemann organizer to become established in the dorsal marginal cells where the future site of the dorsal lip and blastopore will form.

Related Research Articles

<span class="mw-page-title-main">Gastrulation</span> Stage in embryonic development in which germ layers form

Gastrulation is the stage in the early embryonic development of most animals, during which the blastula, or in mammals the blastocyst, is reorganized into a two-layered or three-layered embryo known as the gastrula. Before gastrulation, the embryo is a continuous epithelial sheet of cells; by the end of gastrulation, the embryo has begun differentiation to establish distinct cell lineages, set up the basic axes of the body, and internalized one or more cell types including the prospective gut.

<span class="mw-page-title-main">Neurulation</span> Embryological process forming the neural tube

Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula.

<span class="mw-page-title-main">Neural plate</span>

The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region anterior to the primitive node can be generally referred to as the neural plate. Cells take on a columnar appearance in the process as they continue to lengthen and narrow. The ends of the neural plate, known as the neural folds, push the ends of the plate up and together, folding into the neural tube, a structure critical to brain and spinal cord development. This process as a whole is termed primary neurulation.

<span class="mw-page-title-main">Neurula</span> Embryo at the early stage of development in which neurulation occurs

A neurula is a vertebrate embryo at the early stage of development in which neurulation occurs. The neurula stage is preceded by the gastrula stage; consequentially, neurulation is preceded by gastrulation. Neurulation marks the beginning of the process of organogenesis.

The primitive node is the organizer for gastrulation in most amniote embryos. In birds it is known as Hensen's node, and in amphibians it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center in amphibians, or by the posterior marginal zone in amniotes including birds.

<span class="mw-page-title-main">Primitive streak</span> Structure in early amniote embryogenesis

The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians, the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the broad end towards the anterior, and the narrower region projected to the posterior. The primitive streak forms a longitudinal midline structure in the narrower posterior (caudal) region of the developing embryo on its dorsal side. At first formation, the primitive streak extends for half the length of the embryo. In the human embryo, this appears by stage 6, about 17 days.

<span class="mw-page-title-main">Bone morphogenetic protein 4</span> Human protein and coding gene

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

Chordin is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the CHRD gene.

In the field of developmental biology, regional differentiation is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.

<span class="mw-page-title-main">GDF6</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.

Convergent extension (CE), sometimes called convergence and extension (C&E), is the process by which the tissue of an embryo is restructured to converge (narrow) along one axis and extend (elongate) along a perpendicular axis by cellular movement.

<span class="mw-page-title-main">Fish development</span>

The development of fishes is unique in some specific aspects compared to the development of other animals.

<span class="mw-page-title-main">Homeobox protein goosecoid</span> Protein-coding gene in the species Homo sapiens

Homeobox protein goosecoid(GSC) is a homeobox protein that is encoded in humans by the GSC gene. Like other homeobox proteins, goosecoid functions as a transcription factor involved in morphogenesis. In Xenopus, GSC is thought to play a crucial role in the phenomenon of the Spemann-Mangold organizer. Through lineage tracing and timelapse microscopy, the effects of GSC on neighboring cell fates could be observed. In an experiment that injected cells with GSC and observed the effects of uninjected cells, GSC recruited neighboring uninjected cells in the dorsal blastopore lip of the Xenopus gastrula to form a twinned dorsal axis, suggesting that the goosecoid protein plays a role in the regulation and migration of cells during gastrulation.

The Nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

This article is about the role of Fibroblast Growth Factor Signaling in Mesoderm Formation.

<span class="mw-page-title-main">Edward M. De Robertis</span> American embryologist

Edward Michael De Robertis is an American embryologist and Professor at the University of California, Los Angeles. His work has contributed to the finding of conserved molecular processes of embryonic inductions that result in tissue differentiations during animal development. He was elected to the National Academy of Sciences in 2013, worked for the Howard Hughes Medical Institute for 26 years, and holds a Distinguished Professor at the University of California, Los Angeles. In 2009 Pope Benedict XVI appointed De Robertis to a lifetime position in the Pontifical Academy of Sciences, and in 2022 Pope Francis appointed him Councillor of the Academy for four years.

The Spemann-Mangold organizer is a group of cells that are responsible for the induction of the neural tissues during development in amphibian embryos. First described in 1924 by Hans Spemann and Hilde Mangold, the introduction of the organizer provided evidence that the fate of cells can be influenced by factors from other cell populations. This discovery significantly impacted the world of developmental biology and fundamentally changed the understanding of early development.

A developmental signaling center is defined as a group of cells that release various morphogens which can determine the fates, or destined cell types, of adjacent cells. This process in turn determines what tissues the adjacent cells will form. Throughout the years, various development signaling centers have been discovered.

References

  1. 1 2 Arias, Alfonso Martinez; Steventon, Ben (2018-03-01). "On the nature and function of organizers". Development. 145 (5): dev159525. doi: 10.1242/dev.159525 . ISSN   0950-1991. PMC   5868996 . PMID   29523654.
  2. 1 2 Hemmati-Brivanlou, Ali; Melton, Douglas (1997-01-10). "Vertebrate Embryonic Cells Will Become Nerve Cells Unless Told Otherwise". Cell. 88 (1): 13–17. doi: 10.1016/S0092-8674(00)81853-X . ISSN   0092-8674. PMID   9019398. S2CID   18056689.
  3. 1 2 Levine, Ariel J.; Brivanlou, Ali H. (2007-08-15). "Proposal of a model of mammalian neural induction". Developmental Biology. 308 (2): 247–256. doi:10.1016/j.ydbio.2007.05.036. ISSN   0012-1606. PMC   2713388 . PMID   17585896.
  4. ↑ Sanes, Dan Harvey (2012). Development of the nervous system. Reh, Thomas A., Harris, William A. (William Anthony) (3rd ed.). Amsterdam: Elsevier. p. 9. ISBN   978-0-12-374539-2. OCLC   667213240.
  5. 1 2 Stern, Claudio D. (2005-05-01). "Neural induction: old problem, new findings, yet more questions". Development. 132 (9): 2007–2021. doi: 10.1242/dev.01794 . ISSN   0950-1991. PMID   15829523.
  6. 1 2 Chitnis, A.; Kintner, C. (1995). "Neural induction and neurogenesis in amphibian embryos". Perspectives on Developmental Neurobiology. 3 (1): 3–15. ISSN   1064-0517. PMID   8542254.
  7. 1 2 Sanes, Dan Harvey (2012). Development of the nervous system. Reh, Thomas A., Harris, William A. (William Anthony) (3rd ed.). Amsterdam: Elsevier. p. 11. ISBN   978-0-12-374539-2. OCLC   667213240.
  8. ↑ Guille, Matthew (1999). Molecular Methods in Developmental Biology: Xenopus and Zebrafish. Totowa, New Jersey: Humana Press. p. 27. ISBN   978-0-89603-790-8.
  9. ↑ Sasai, Yoshiki; Lu, Bin; Steinbeisser, Herbert; Geissert, Douglas; Gont, Linda K.; De Robertis, Eddy M. (1994-12-02). "Xenopus chordin: A Novel Dorsalizing Factor Activated by Organizer-Specific Homeobox Genes". Cell. 79 (5): 779–790. doi:10.1016/0092-8674(94)90068-X. ISSN   0092-8674. PMC   3082463 . PMID   8001117.
  10. 1 2 Sanes, Dan Harvey (2012). Development of the nervous system. Reh, Thomas A., Harris, William A. (William Anthony) (3rd ed.). Amsterdam: Elsevier. p. 15. ISBN   978-0-12-374539-2. OCLC   667213240.
  11. ↑ Rogers, Crystal; Moody, Sally A.; Casey, Elena (2009-09-11). "Neural induction and factors that stabilize a neural fate". Birth Defects Research Part C: Embryo Today: Reviews. 87 (3): 249–262. doi:10.1002/bdrc.20157. ISSN   1542-975X. PMC   2756055 . PMID   19750523.
  12. ↑ Muñoz-Sanjuán, Ignacio; Brivanlou, Ali H. (2002-04-01). "Neural induction, the default model and embryonic stem cells". Nature Reviews Neuroscience. 3 (4): 271–280. doi:10.1038/nrn786. ISSN   1471-0048. PMID   11967557. S2CID   23551830.
  13. ↑ Weinstein, Daniel; Hemmati-Brivanlou, Ali (1999). "Neural Induction". Annual Review of Cell and Developmental Biology. 15: 411–433. doi:10.1146/annurev.cellbio.15.1.411. PMID   10611968.
  14. ↑ Carron, Clémence; Shi, De-Li (2016). "Specification of anteroposterior axis by combinatorial signaling during Xenopus development". Wiley Interdisciplinary Reviews. Developmental Biology. 5 (2): 150–168. doi:10.1002/wdev.217. ISSN   1759-7692. PMID   26544673. S2CID   13504185.
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