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Cited by 39Developmental Biology and Gene RegulationCell Adhesion Molecules ResearchNeurogenesis and neuroplasticity mechanisms

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Cadherins in early neural development

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Punovuori, Karolina, Malaguti, Mattias, Lowell, Sally·2021·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-021-03815-9PMC PMC8164589
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Abstract

During early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

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Figures

Fig. 1 Structure of the cadherin domains of mouse Cdh1. a Two cadherin domains from mouse E-cadherin (EC2, EC3), forming seven-stranded β-sandwiches. Binding of three calcium ions (displayed in emerald green) is mediated at the aspartate and glutamate-rich interface of the two domains. Further calcium ions are visible at the interface of these domains with neighbouring cadherin domains. b–c Trans-interaction between two E-cadherin ectodomains (EC1-5 for green chain, EC1-4 for orange chain). A conserved residue (Trp2) in EC1 interacts with a hydrophobic pocket on the opposite EC1 domain. Crystal structure from [23] (PDB: 3Q2V) visualised with Mol*
Fig. 1 Structure of the cadherin domains of mouse Cdh1. a Two cadherin domains from mouse E-cadherin (EC2, EC3), forming seven-stranded β-sandwiches. Binding of three calcium ions (displayed in emerald green) is mediated at the aspartate and glutamate-rich interface of the two domains. Further calcium ions are visible at the interface of these domains with neighbouring cadherin domains. b–c Trans-interaction between two E-cadherin ectodomains (EC1-5 for green chain, EC1-4 for orange chain). A conserved residue (Trp2) in EC1 interacts with a hydrophobic pocket on the opposite EC1 domain. Crystal structure from [23] (PDB: 3Q2V) visualised with Mol*CC BY · PubMed Central
Fig. 2 Cadherin subfamilies and representative members. Representative members of the eight cadherin subfamilies described in the text. The plasma membrane is illustrated as two parallel horizontal lines. Mm Mus musculus, Dm Drosophila melanogaster, CA cadherin domain, TM transmembrane domain, CCD cadherin cytoplasmic domain, NC non-chordate domain, CE cysteine-rich EGF-like domain, LAG laminin globular domain, LEGF laminin-type EGF-like domain, HR hormone receptor motif, GPS GPCR proteolytic site, white: other regions
Fig. 2 Cadherin subfamilies and representative members. Representative members of the eight cadherin subfamilies described in the text. The plasma membrane is illustrated as two parallel horizontal lines. Mm Mus musculus, Dm Drosophila melanogaster, CA cadherin domain, TM transmembrane domain, CCD cadherin cytoplasmic domain, NC non-chordate domain, CE cysteine-rich EGF-like domain, LAG laminin globular domain, LEGF laminin-type EGF-like domain, HR hormone receptor motif, GPS GPCR proteolytic site, white: other regionsCC BY · PubMed Central
Fig. 3 Phylogeny and structure of cadherin and cadherin-like domains. a Number of InterPro database entries for “Cadherin” and “Cadherin-like” protein domains, sorted taxonomically. Phylogenetic relationships of the described clades are based on [43–45]. InterPro data retrieved in May 2020. b Structural comparison of two CA domains of human CDH1 with two CDHL domains of mouse Cdh23 and Staphylococcus aureus SraP. Calcium ions are displayed as wireframe structures. Crystal structures from [46] (PDB: 3MVS), [47] (PDB: 2O72), [42] (PDB: 4M03), visualised with Swiss-PdbViewer [48] and aligned with the CA/CDHL domains on the right of the image in similar orientation
Fig. 3 Phylogeny and structure of cadherin and cadherin-like domains. a Number of InterPro database entries for “Cadherin” and “Cadherin-like” protein domains, sorted taxonomically. Phylogenetic relationships of the described clades are based on [43–45]. InterPro data retrieved in May 2020. b Structural comparison of two CA domains of human CDH1 with two CDHL domains of mouse Cdh23 and Staphylococcus aureus SraP. Calcium ions are displayed as wireframe structures. Crystal structures from [46] (PDB: 3MVS), [47] (PDB: 2O72), [42] (PDB: 4M03), visualised with Swiss-PdbViewer [48] and aligned with the CA/CDHL domains on the right of the image in similar orientationCC BY · PubMed Central
Fig. 4 Generalised morphological events of neurulation leading to neural tube closure. Transverse view. Neurulation begins in the flat neural plate, which generates lineages of the central nervous system. It is flanked on either side by the neural plate border and non-neural ectoderm. As neurulation progresses, the neural plate thickens, stratifies and begins to fold, while a ventral hinge point is formed at the notochord, a mesodermal tissue. The neural plate borders elevate, becoming the neural crest. As the neural tube fuses dorsally, neural crest cells migrate out of it, going on to form lineages of the peripheral nervous system. Closure of the nascent neural tube disconnects it from the overlying epidermis
Fig. 4 Generalised morphological events of neurulation leading to neural tube closure. Transverse view. Neurulation begins in the flat neural plate, which generates lineages of the central nervous system. It is flanked on either side by the neural plate border and non-neural ectoderm. As neurulation progresses, the neural plate thickens, stratifies and begins to fold, while a ventral hinge point is formed at the notochord, a mesodermal tissue. The neural plate borders elevate, becoming the neural crest. As the neural tube fuses dorsally, neural crest cells migrate out of it, going on to form lineages of the peripheral nervous system. Closure of the nascent neural tube disconnects it from the overlying epidermisCC BY · PubMed Central
Fig. 5 E-cadherin is exchanged for N-cadherin as the pluripotent epiblast forms neuroectoderm or mesoderm. E-cadherin in the epiblast may prime cells for future activation of Wnt [189, 197]. N-cadherin in the neuroectoderm dampens low levels of FGF that would otherwise have anti-neural activity [189]. It remains an open question whether the high levels of FGF or other differences in context in the emerging mesoderm override the FGF-dampening effects of N-cadherin
Fig. 5 E-cadherin is exchanged for N-cadherin as the pluripotent epiblast forms neuroectoderm or mesoderm. E-cadherin in the epiblast may prime cells for future activation of Wnt [189, 197]. N-cadherin in the neuroectoderm dampens low levels of FGF that would otherwise have anti-neural activity [189]. It remains an open question whether the high levels of FGF or other differences in context in the emerging mesoderm override the FGF-dampening effects of N-cadherinCC BY · PubMed Central

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Research works printed but not linked: 2

  1. Sterneckert J, Stehling M, Bernemann C, Araúzo-Bravo MJ, Greber B, Gentile L et al (2010) Neural induction intermediates exhibit distinct roles of Fgf signaling. Stem Cells 28:1772–1781 · DOI
  2. Kohei Hatta MT (1986) Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320:447–449 · DOI

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Metadata

Authors
Punovuori, K., Malaguti, M., & Lowell, S.
Affiliations
  • University of Helsinki (FI)
  • MRC Centre for Regenerative Medicine (GB)
Corresponding author
Lowell, Sally
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2021-04-01
Volume
78
Issue
9
Pages
4435-4450
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-021-03815-9
PMC
PMC8164589
OpenAlex
W3142970685
Cited by
39
References
206
Citations by year
2026: 8 · 2025: 9 · 2024: 12 · 2023: 6 · 2022: 3 · 2021: 1
FWCI
0.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, other-oa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
Wellcome Trust (WT103789AIA)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
cadherins, neural tube morphogenesis, adhesion molecules, cell fate determination, cell differentiation, signaling, transcription factors
MeSH terms
Animals, Cell Adhesion, Cell Differentiation, Humans, Neural Crest, Transcription Factors, Signal Transduction, Cadherins, Evolution, Molecular, Neurogenesis

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