Inter-rhombomeric interactions reveal roles for fibroblast growth factors signaling in segmental regulation of EphA4 expression

Dev Dyn. 2020 Mar;249(3):354-368. doi: 10.1002/dvdy.101. Epub 2019 Aug 22.


Background: The basic ground plan of vertebrate hindbrain is established through a process of segmentation, which generates eight transient lineage-restricted cellular compartments called rhombomeres (r). The segments adopt distinct individual identities in response to axial patterning signals. It is unclear whether signaling between rhombomeres plays a conserved role in regulating segmental patterning during hindbrain development.

Results: Using tissue manipulations of rhombomeres in chicken embryos, we have uncovered roles for r2 and r4 in regulating the expression of EphA4 in r3 and r5. Perturbations of signaling pathways reveal that these regulatory inputs from r2 and r4 into EphA4 expression are mediated independent of inputs from Krox20 through cues involving fibroblast growth factor (FGF) signaling. These interactions are stage dependent and are set up in embryos with <10 somites.

Conclusions: We show that r2 and r4 function as temporally dynamic signaling centers in the early patterning of adjacent hindbrain segments and this activity is dependent upon the FGF pathway. These results reveal that inter-rhombomeric signaling is a conserved feature of the regulatory networks that control the specification of individual rhombomere identities in vertebrate hindbrain segmentation. However, the timing of when restricted domains of FGF signaling are coupled to formation of r4 may vary between the species.

Keywords: Eph receptors; EphA4; FGF signaling; hindbrain segmentation; rhombomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chick Embryo
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • In Situ Hybridization
  • Receptor, EphA4 / genetics
  • Receptor, EphA4 / metabolism*
  • Receptors, Eph Family / genetics
  • Receptors, Eph Family / metabolism
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Rhombencephalon / embryology
  • Rhombencephalon / metabolism*


  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • Receptor, EphA4
  • Receptors, Eph Family