Brains Emerging: On Modularity and Self-organisation of Neural Development In Vivo and In Vitro

  • Paul Gottlob LayerEmail author


Molecular developmental biology has expanded our conceptions of gene actions, underpinning that embryonic development is not only governed by a set of specific genes, but as much by space–time conditions of its developing modules (determinate vs. regulative development; or, nature vs. nurture discussion). Typically, formation of cellular spheres, their transformation into planar epithelia, followed by tube formations and laminations are modular steps leading to the development of nervous tissues. Thereby, actions of organising centres, morphogenetic movements (in- and evaginations), inductive events between epithelia, tissue polarity reversal, widening of epithelia, and all these occurring orderly in space and time, are driving forces of emergent laminar neural tissues, e.g. the vertebrate retina. Analyses of self-organisational formation of retina-like 3D structures from dispersed cells (so-called retinal spheroids, also called retinal organoids) under defined cell culture conditions (in vitro) demonstrate that not only particular genetic networks, but—at least as important—the applied culture conditions (in vitro constraints) define phenotypes of emergent tissues. Such in vitro approaches allow assigning emerging tissue formation to ground-laying genetic networks separately from contributions by conditional constraints.



My teachers E. E. Bruchmann (Hohenheim), F. Hucho (Konstanz), E. Shooter (Stanford), H. Meinhardt and A. Gierer (Tübingen) have ignited my passion for science and paved my way into developmental biology research. I thank my students and colleagues G. Bachmann, A. Bytyqi, A. Daus, F. Frohns, M. Reinicke, M. Rieke, A. Robitzki, A. Rothermel, L. Sperling, G. Thangaraj, G. Vollmer and E. Willbold, who have—in spite of difficult infrastructures—promoted our spheroid research with great stamina and enthusiasm. I thank Lynda Wright (Madison, WI) for her careful reading and comments. Editorial assistance by the Chief Editors U. Lüttge and L. H. Wegner is greatly acknowledged.


  1. Alegado RA, Brown LW, Cao S, Dermenjian RK, Zuzow R, Fairclough SR et al (2012) A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals. eLife 1:e00013Google Scholar
  2. Bytyqi AH, Bachmann G, Rieke M, Paraoanu LE, Layer PG (2007) Cell-by-cell reconstruction in reaggregates from neonatal gerbil retina begins from the inner retina and is promoted by retinal pigmented epithelium. Eur J Neurosci 26:1560–1574CrossRefGoogle Scholar
  3. Chalmers DJ, Jackson F (2001) Conceptual analysis and reductive explanation. Philos Rev 110:315–361CrossRefGoogle Scholar
  4. Cremer T, Cremer C, Lichter P (2014) Recollections of a scientific journey published in human genetics: from chromosome territories to interphase cytogenetics and comparative genome hybridization. Hum Genet 133:403–416CrossRefGoogle Scholar
  5. Eldred MK, Charlton-Perkins M, Muresan L, Harris WA (2017) Self-organising aggregates of zebrafish retinal cells for investigating mechanisms of neural lamination. Development 144:1097–1106. Scholar
  6. Eiraku M et al (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472:51–56CrossRefGoogle Scholar
  7. Franze K (2013) The mechanical control of nervous system development. Development 140:3069–3077. Scholar
  8. Fromm J (2005) Types and forms of emergence. Cornell University Library. arXiv:nlin/0506028
  9. Gierer A (2012) The hydra model—a model for what? Int J Dev Biol 56:437–445CrossRefGoogle Scholar
  10. Gilbert SF (2016) Developmental biology, 11th edn. Sinauer Ass, MA, USAGoogle Scholar
  11. Götz M, Wizenmann A, Reinhardt S, Lumsden A, Price J (1996) Selective adhesion of cells from different telencephalic regions. Neuron 16:551–564CrossRefGoogle Scholar
  12. Grosberg RK, Strathmann RR (2007) The evolution of multicellularity: a minor major transition. Annu Rev Ecol Evol Syst 38:621–654CrossRefGoogle Scholar
  13. Haeckel E (1904, 1998). Kunstformen der Natur. Neudruck der Erstausgabe in Faksimile. Leipzig, Wien, Bibliogr Inst. ISBN 3-7913-1979-5Google Scholar
  14. Huch M, Knoblich JA, Lutolf MP, Martinez-Arias A (2017) The hope and the hype of organoid research. Development 144:938–941. Scholar
  15. Jahn I (2000) Geschichte der Biologie, 3rd edn. Spektrum Akad. Verl. Heidelberg, BerlinGoogle Scholar
  16. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–381CrossRefGoogle Scholar
  17. Layer PG, Alber R (1990) Patterning of chick brain vesicles as revealed by peanut agglutinin and cholinesterases. Development 109:613–624PubMedGoogle Scholar
  18. Layer PG, Willbold E (1994) Regeneration of the avian retina by retinospheroid technology. Prog Ret Res 1994(13):197–230CrossRefGoogle Scholar
  19. Layer PG, Araki M, Vogel-Höpker A (2010) New concepts for reconstruction of retinal and pigment epithelial tissues. Exp Rev Ophthalmol 5:523–544CrossRefGoogle Scholar
  20. Lenz M, Witten TA (2017) Geometrical frustration yields fibre formation in self-assembly. Nat Phys 13:1100–1104. Scholar
  21. Lumsden A, Keynes R (1989) Segmental patterns of neuronal development in the chicken hindbrain. Nature 337:424–428CrossRefGoogle Scholar
  22. McFall-Ngai M, Hadfield MG, Bosch TC, Carey HV, Domazet-Loso T, Douglas AE et al (2013) Animals in a bacterial world, a new imperative for the life sciences. Proc Natl Acad Sci USA 110:3229–3236. Scholar
  23. Meyer MS et al (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci USA 106:16698–16703CrossRefGoogle Scholar
  24. Nakagawa S, Takada S, Takada R, Takeichi M (2003) Identification of the laminar inducing factor: Wnt-signal from the anterior rim induces correct laminar formation of the neural retina in vitro. Dev Biol 260:414–425CrossRefGoogle Scholar
  25. Puelles L (2001) Brain segmentation and forebrain development in amniotes. Brain Res Bull 55:695–710CrossRefGoogle Scholar
  26. Reichenbach A, Bringmann A (2013) New functions of Müller cells. Glia 61:651–678CrossRefGoogle Scholar
  27. Rieke M, Bytyqi A, Frohns F, Layer PG (2018). Reconstructing mammalian retinal tissue: Wnt3a regulates laminar polarity in retinal spheroids from neonatal Mongolian rats, while RPE promotes cell differentiation. Int J Stem Cell Res Therapy.
  28. Steinberg MS (2007) Differential adhesion in morphogenesis: a modern view. Curr Opin Genet Dev 17:281–286CrossRefGoogle Scholar
  29. Strauss BS (2016) Beadle and Tatum and the origins of molecular biology. Nat Rev Mol Cell Biol 17:266. Scholar
  30. van de Werken HJG, Haan JC, Feodorova Y, Bijos D, Weuts A et al (2017) Small chromosomal regions position themselves autonomously according to their chromatin class. Genome Res 27:922–933. Scholar
  31. Vollmer G, Layer PG, Gierer A (1984) Reaggregation of embryonic chick retina cells: pigment epithelial cells induce a high order of stratification. Neurosci Letts 48:191–196CrossRefGoogle Scholar
  32. Weikert T, Rathjen FG, Layer PG (1990) Developmental maps of acetylcholinesterase and G4-antigen of the early chicken brain: long distance tracts originate from AChE-producing cell bodies. J Neurobiol 21:482–498 CrossRefGoogle Scholar
  33. Wilson HV (1905) On some phenomena of coalescence and regeneration in sponges. J Exp Zool 5:245–258. Scholar
  34. Zhong X et al (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.DarmstadtGermany

Personalised recommendations