Developmental Biology
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Overview
Early embryonic pattern formation: I. Cleavage
According to theories that still dominate in the textbooks, mammalian morulae lack any pre-patterns with respect to the future body axes, and the only developmentally relevant process taking place during these early phases is the determination of the two first distinct populations of cells, trophoblast and embryoblast (inner cell mass). Stochastic positioning of (equipotent) blastomeres, at the surface or in the center of the morula (i.e. surrounded by other cells), would be decisive for triggering differentiation into the two divergent directions (inside-outside and polarization hypothesis). Body axes (dorso-ventral, cranio-caudal/anterior-posterior) would be determined much later, by so far unknown mechanisms, and it is often speculated that some type of instruction provided by the uterus at implantation must be essential for this.
However, our data on cleavage and blastocyst formation in the rabbit suggested to us already years ago (in agreement with some classical observations) that at least the determination of one of the main body axes, the dorso-ventral axis, starts already during cleavage so that it seems to depend on cytoplasmic informations already inherited from the zygote. On the basis of morphological and histochemical findings we have postulated that morulae possess a proliferative center as well as a center of early differentiation, positioned at (perhaps not exactly) opposite poles, and that trophoblast differentiation and subsequent blastocyst cavity formation start at the latter center thus defining the future abembryonic pole. The positioning of the blastocyst cavity and of the inner cell mass/embryonic knot would thus be pre-determined and would not come about stochastically, and so the embryonic-abembryonic axis would be positioned (from which the dorso-ventral axis is derived). This contradicts the above-mentioned inside-outside/polarization hypothesis (which had been developed on the basis of experiments done in the mouse) at least in its original strict version which can explain only a radial organisation. However, as the impressive regulative capacities of early mammalian embryos clearly show, axis pre-determination is in the beginning not rigid but flexible. Interestingly, this (flexible) axis pre-determination as postulated by us a long time ago seems to receive confirmation from recent investigations done by certain groups of investigators in the mouse.
Early embryonic pattern formation: II. Stem cell colonies
Not only totipotent cells (zygote, blastomeres) but also pluripotent/omnipotent stem cells (ES cells, iPS cells) are capable of initiating early embryonic pattern formation (individuation) processes if appropriate environmental conditions are provided. Colonies of ES cells can initiate cell biological elements of gastrulation (the process which is decisive for the formation of the germ layers as well as for laying down the basic body plan), in a relatively ordered way depending on culturing conditions. This has also been shown in embryoid bodies. The degree of order that develops (axis formation, basic body plan) appears to depend on asymmetry cues that in normal development are derived from the zygote but can be replaced experimentally by external, artificial asymmetries (in colonies of ES or iPS cells) or by host cells (tetraploid complementation). These aspects are not only of interest for the developmental biologist but are also relevant for the ethics of stem cell use (see research topic 1: stem cells).
Early embryonic pattern formation: III. Not dependent on implantation
Early embryonic pattern formation processes (axis determination, individuation) do not depend on instruction obtained at implantation of the blastocyst, as shown by our experiments on the blockage of implantation by proteinase inhibitors in the rabbit (see research topic 4). This contradicts a hypothesis which had been derived from observations made in the mouse and which has survived surprisingly long and has often been cited even in ethical considerations; according to recent findings, however, it is incorrect even for the mouse.
List of Publications
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DENKER, H.-W.:
Embryoids, models, embryos? We need to take a new look at legal norms concerning the beginning of organismic development.
Molec. Hum. Reprod. 30(1): gaad047 (2024). DOI: 10.1093/molehr/gaad047
PubMed
MHR
pdf-download (615 KB)
DENKER, H.-W.:
Stem Cell-Derived Organoids, Embryoids, and Embryos: Advances in Organismic Development In Vitro Force Us to Re-Focus on Ethical and Legal Aspects of Model Choice.
Organoids 2: 231-238 (2023). DOI: 10.3390/organoids2040018
Organoids Website
pdf-download (247 KB)
DENKER, H.-W.:
Wir brauchen eine Neudefinition des Begriffs "Embryo".
Deutsches Ärzteblatt 120 (33-34): A-1383 / B-1191 (21. August 2023).
Deutsches Ärzteblatt
pdf-download (315 KB)
DENKER, H.-W.:
Autonomy in Stem Cell-Derived Embryoids.
Encyclopedia Platform, encyclopedia.pub/14708 (2021).
Encyclopedia
DENKER, H.-W.:
Autonomy in the Development of Stem Cell-Derived Embryoids:
Sprouting Blastocyst-Like Cysts, and Ethical Implications.
Cells 10: 1461 (2021) (Open Access). DOI: 10.3390/cells10061461
PubMed
Cells Website
pdf-download (1.54 MB)
DENKER, H.-W.:
Blastocyst-like cysts sprouting autonomously from stem cell cultures: Self-organization and implantation potential.
(Comment on: KIME, C., KIYONARI, H., OHTSUKA, S., KOHBAYASHI, E., ASAHI, M., YAMANAKA, S., TAKAHASHI, M. & TOMODA, K.: Induced 2C Expression and Implantation-Competent Blastocyst-like Cysts from Primed Pluripotent Stem Cells. Stem Cell Reports 13:485-498, 2019).
Preprint (2020). DOI: 10.13140/RG.2.2.34000.74242
pdf-download (311 KB)
DENKER, H.-W.:
Recent embryo twinning data prompt reconsideration of theories on a crucial role of segregation of oocyte cytoplasmic constituents in mammals.
(Comment on: CASSER, E., WDOWIK, S., ISRAEL, S., WITTEN, A., SCHLATT, S., NORDHOFF, V., BOIANI, M.: Differences in blastomere totipotency in 2-cell mouse embryos are a maternal trait mediated by asymmetric mRNA distribution. Molec. Hum. Reproduct. 25/11, 729-744, 2019. DOI: 10.1093/molehr/gaz051)
Molec. Hum. Reprod. 26: 193-198 (2020). DOI: 10.1093/molehr/gaaa005
PubMed
MHR
PDF-Download AOV (214 KB)
DENKER, H.-W.:
Embryonen, Embryoide, Gastruloide... Ethische Aspekte zur Selbstorganisation und zum Engineering von Stammzellkolonien und Embryonen.
In: M. Rothhaar, M. Hähnel, R. Kipke (Eds.): Der manipulierbare Embryo. Potentialitäts- und Speziesargumente auf dem Prüfstand. Münster: Mentis (Brill), 2018, pp. 15-47. DOI: 10.30965/9783957438393_003 (Open Access)
Mentis (Brill) (Open Access)
Google Scholar
Abstract (40 KB)
pdf-download (196 KB)
DENKER, H.-W.:
Embryonen und Embryoide: Gedanken eines Entwicklungsbiologen zu ethischen Implikationen von Autonomie und Machbarkeit.
(Lecture) Der manipulierbare Embryo: Potentialitäts- und Speziesargumente auf dem Prüfstand (Auftakttagung zum BMBF-Projekt "Der manipulierbare Embryo"), Eichstätt, Katholische Universität Eichstätt-Ingolstadt, 3.-5. Nov. 2016.
lecture pdf (4.70 MB)
DENKER, H.-W.:
Self-Organization of Stem Cell Colonies and of Early Mammalian Embryos: Recent Experiments Shed New Light on the Role of Autonomy vs. External Instructions in Basic Body Plan Development.
Cells 5(4): E39 (2016) (Open access). DOI: 10.3390/cells5040039
PubMed
Cells Website
pdf-download (5.16 MB)
DENKER, H.-W.:
„Totipotency“ of stem cells: Plasticity vs. self-organization capacity
(Comment on: ISHIUCHI, T., ENRIQUEZ-GASCA, R., MIZUTANI, E., BOSKOVIC, A., ZIEGLER-BIRLING, C., RODRIGUEZ-TERRONES, D., WAKAYAMA, T., VAQUERIZAS, J.M., TORRES-PADILLA, M.E.: Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly. Nature Struct. Mol. Biol. 22: 662-671, 2015).
Preprint (2015). DOI: 10.13140/RG.2.2.15761.25441
pdf-download (113 KB)
DENKER, H.-W.:
Stem Cell Terminology and 'Synthetic' Embryos: A New Debate on Totipotency, Omnipotency, and Pluripotency and How It Relates to Recent Experimental Data
Cells Tissues Organs 199: 221-227 (2014).
PubMed
CTO Website (free access)
DENKER, H.-W.:
Comment on G. Herranz: The timing of monozygotic twinning: a criticism of the common model. Zygote (2013).
Zygote 23: 312-314 (2015).
PubMed
Zygote
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LITTWIN, T., DENKER, H.-W.:
Segregation during cleavage in the mammalian embryo? A critical comparison of whole-mount/CLSM and section immunohistochemistry casts doubts on segregation of axis-relevant leptin domains in the rabbit.
Histochemistry and Cell Biology 135: 553-570 (2011).
PubMed
SpringerLink
MARANCA-HÜWEL, B., DENKER, H.-W.:
Epithelial-mesenchymal transition in rhesus monkey embryonic stem cell colonies: the role of culturing conditions.
In Vitro Cell. Dev. Biol. - Animal 46(6): 516-528 (2010).
PubMed pdf-download (951 KB; Please note the copyright regulations of the SIVBThis material has been published in In Vitro Cell. Dev. Biol. - Animal 46(6): 516-528 (2010), the only accredited archive of the content that has been certified and accepted after peer review. Copyright and all rights therein are retained by the Society for In Vitro Biology. This material may not be copied or e-posted without explicit permission of the copyright owner.
For more information about Reproduction Permission for this article, please visit the SIVB website by clicking on the link above or anywhere on this infobox.!)
DENKER, H.-W.:
Induced pluripotent stem cells: How to deal with the developmental potential.
Reproductive BioMedicine Online 19 Suppl. 1: 34-37 (2009).
PubMed
pdf-download (287 KB)
RBMOnline
DENKER, H.-W.:
Human embryonic stem cells:
The real challenge for research as well as for bioethics is still ahead of us.
Cells Tissues Organs 187: 250-256 (2008).
PubMed
pdf-download (155 KB)
DENKER, H.-W., BEHR, R., HENEWEER, C., VIEBAHN, C., THIE, M.:
Epithelial-mesenchymal transition in rhesus monkey embryonic stem cell colonies: a model for processes involved in gastrulation?
Cells Tissues Organs 185: 48-50 (2007). PubMed pdf-download (162 KB)
BEHR, R., HENEWEER, C., VIEBAHN, C., DENKER, H.-W., THIE, M.:
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation.
Stem Cells 23: 805-816 (2005). PubMed pdf-download (559 KB)
DENKER, H.-W.:
Early human development: New data raise important embryological and ethical questions relevant for stem cell research.
Naturwissenschaften 91: 1-21 (2004). DOI: 10.1007/s00114-003-0490-8
PubMed
pdf-download (853 KB)
DENKER, H.-W.:
Embryonale Stammzellen als entwicklungsbiologisches Modell: Frühembryonale Musterbildung und Totipotenz.
In: Die Frühphase der Entwicklung des Menschen. Embryologische und ethische Aspekte. (G. Rager /A. Holderegger, Eds.) (Reihe: Herausforderung und Besinnung, Band 19). Universitätsverlag Freiburg/Schweiz, ISBN 3-7278-1416-0 (distributed by: Academic Press, Fribourg/Switzerland), 2003, pp. 23-71. pdf-download (104 MB)
DENKER, H.-W.:
Embryonic stem cells: An exciting field for basic research and tissue engineering, but also an ethical dilemma?
Cells Tissues Organs 165: 246-249 (1999).
pdf-download (188 KB)
PubMed
CTO Website (free access)
DENKER, H.-W. and PEDERSEN, R.A.:
The use of intracellular horseradish peroxidase (HRP) injection for cell lineage studies in early mammalian development.
(Abstr.) XXVI. Symposium Gesellschaft f. Histochemie, Maastricht 1984
pdf-download (957 KB)
DENKER, H.-W., PEDERSEN, R.A., STRUNCK, B.:
"Cell lineage" und Zell- Zell- bzw. Zell-Matrix-Interaktionen in der frühen Säugetierembryogenese: Mikro-Injektionsversuche.
(Abstr.) Symposium "Oogenese, Embryogenese und Musterbildung" (Gesellschaft für Entwicklungsbiologie, Deutsche Forschungsgemeinschaft), Institut für Biologie I (Zoologie), Freiburg i.Br., 9.-10. März 1984.
pdf-download (1.53 MB)
DENKER, H.-W.:
Cell lineage, determination and differentiation in earliest developmental stages in mammals.
In: Problems of the Keimbahn. New Work on Mammalian Germ Cell Lineage. (W. Hilscher, ed.) (Bibliotheca anat., No. 24). Basel: S. Karger AG, 1983, ISBN: 978-3-8055-3614-1, pp. 22-58.
PubMed
pdf-download (24.7 MB)
MEINSHAUSEN, E. und DENKER, H.-W.:
Entwicklungsleistungen von Kaninchenembryonen trotz Hemmung der Anheftung in utero.
Verh. Anat. Ges. 77, Anat. Anz. Suppl. 154, 421-423 (1983). pdf-download (1.16 MB)
DENKER, H.-W. and MEINSHAUSEN, E.:
Continued differentiation of mammalian embryos in utero after blockage of implantation.
Abstract No. 22, XVth EDBO International Embryological Conference, Strasbourg, 1982. DOI: 10.13140/RG.2.2.28742.91201
abstract (376 KB)
poster (11.8 MB)
DENKER, H.-W.:
Cell lineage, determination and differentiation in earliest developmental stages.
(Abstr.) Sixth European Anatomical Congress, Hamburg 1981. Acta anat. (Basel) 111, 31 (1981)
pdf-download (456 KB)
DENKER, H.-W.:
The determination of trophoblast and embryoblast cells during cleavage in the mammal: new trends in the interpretation of the mechanisms.
Verh. Anat. Ges. 75, Anat. Anz. Suppl. 150, 445-448 (1981). pdf-download (1.39 MB)
DENKER, H.-W.:
Entwicklungsphysiologie des frühen Säugetierkeims. (Hauptreferat)
(Abstr.) Tagung der Gesellschaft für Entwicklungsbiologie, Heidelberg, April 1979
pdf-download (541 KB)
DENKER, H.-W., ENG, L.A., MOOTZ, U. and HAMNER, C.E.:
Studies on the early development and implantation in the cat. I. Cleavage and blastocyst formation.
Anat. Anz. 144, 457-468 (1978). PubMed pdf-download (4.41 MB)
DENKER, H.-W.:
Formation of the blastocyst: determination of trophoblast and embryonic knot.
Current Topics in Pathology (E. Grundmann und H.W. Kirsten, eds.) Vol. 62: Developmental Biology and Pathology (A. Gropp und K. Benirschke, Vol.-eds.). Berlin-Heidelberg-New York: Springer-Verlag, 1976, pp. 59-79.
PubMed
SpringerLink
pdf-download (8.17 MB)
Abstract (58 KB)
DENKER, H.-W.:
Furchung beim Säugetier: Differenzierung von Trophoblast- und Embryonalknotenzellen.
Verh. Anat. Ges. 66, Anat. Anz. Suppl. 130, 267-272 (1972). PubMed pdf-download (2.27 MB)
DENKER, H.-W.:
Discussion Remark to: J.G. Mulnard: Manipulation of cleaving mammalian embryo with special reference to a time-lapse cinematographic analysis of centrifuged and fused mouse eggs.
In: Schering Symposium on Intrinsic and Extrinsic Factors in Early Mammalian Development, Venice 1970 (Gerhard Raspé, Ed.). Oxford etc.: Pergamon Press / Vieweg (= Advances in the Biosciences 6, ISBN 008 0175716 and 3 528 076887), 1971, pp. 255-277 (Discussion pp. 275-277).
pdf-download (1.08 MB)
DENKER, H.-W.:
Topochemie hochmolekularer Kohlenhydratsubstanzen in Frühentwicklung und Implantation des Kaninchens.
II. Beiträge zu entwicklungsphysiologischen Fragestellungen.
Zool. Jb. Physiol. 75, 246-308 (1970). pdf-download (23.1 MB)
DENKER, H.-W.:
Topochemie hochmolekularer Kohlenhydratsubstanzen in Frühentwicklung und Implantation des Kaninchens.
Dissertation, Naturwissenschaftliche Fakultät der Philipps-Universität, Marburg/Lahn 1969. German National Library