Downstream mediators of Ten-m3 signalling in the developing visual pathway

BMC Neurosci. 2017 Dec 6;18(1):78. doi: 10.1186/s12868-017-0397-5.


Background: The formation of visuotopically-aligned projections in the brain is required for the generation of functional binocular circuits. The mechanisms which underlie this process are unknown. Ten-m3 is expressed in a broad high-ventral to low-dorsal gradient across the retina and in topographically-corresponding gradients in primary visual centres. Deletion of Ten-m3 causes profound disruption of binocular visual alignment and function. Surprisingly, one of the most apparent neuroanatomical changes-dramatic mismapping of ipsilateral, but not contralateral, retinal axons along the representation of the nasotemporal retinal axis-does not correlate well with Ten-m3's expression pattern, raising questions regarding mechanism. The aim of this study was to further our understanding of the molecular interactions which enable the formation of functional binocular visual circuits.

Methods: Anterograde tracing, gene expression studies and protein pull-down experiments were performed. Statistical significance was tested using a Kolmogorov-Smirnov test, pairwise-fixed random reallocation tests and univariate ANOVAs.

Results: We show that the ipsilateral retinal axons in Ten-m3 knockout mice are mismapped as a consequence of early axonal guidance defects. The aberrant invasion of the ventral-most region of the dorsal lateral geniculate nucleus by ipsilateral retinal axons in Ten-m3 knockouts suggested changes in the expression of other axonal guidance molecules, particularly members of the EphA-ephrinA family. We identified a consistent down-regulation of EphA7, but none of the other EphA-ephrinA genes tested, as well as an up-regulation of ipsilateral-determinants Zic2 and EphB1 in visual structures. We also found that Zic2 binds specifically to the intracellular domain of Ten-m3 in vitro.

Conclusion: Our findings suggest that Zic2, EphB1 and EphA7 molecules may work as effectors of Ten-m3 signalling, acting together to enable the wiring of functional binocular visual circuits.

Keywords: Binocular vision; Contralateral; EphA7; Ipsilateral; Neural development; Retina; Retinotopic mapping; Teneurin/Odz; Zic2.

MeSH terms

  • Animals
  • Axons / metabolism
  • Cell Enlargement
  • Functional Laterality
  • Gene Expression Regulation, Developmental
  • Geniculate Bodies / cytology
  • Geniculate Bodies / growth & development
  • Geniculate Bodies / metabolism
  • Intracellular Space / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptor, EphA7 / metabolism
  • Receptor, EphB1 / metabolism
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism
  • Superior Colliculi / cytology
  • Superior Colliculi / growth & development
  • Superior Colliculi / metabolism
  • Transcription Factors / metabolism
  • Vision, Binocular / physiology
  • Visual Pathways / cytology
  • Visual Pathways / growth & development*
  • Visual Pathways / metabolism*


  • Membrane Proteins
  • Nerve Tissue Proteins
  • Tenm3 protein, mouse
  • Transcription Factors
  • Zic2 protein, mouse
  • Receptor, EphA7
  • Receptor, EphB1
  • epha7 receptor, mouse