Celsr3 and Fzd3 Organize a Pioneer Neuron Scaffold to Steer Growing Thalamocortical Axons

Cereb Cortex. 2016 Jul;26(7):3323-34. doi: 10.1093/cercor/bhw132. Epub 2016 May 11.


Celsr3 and Fzd3 regulate the development of reciprocal thalamocortical projections independently of their expression in cortical or thalamic neurons. To understand this cell non autonomous mechanism further, we tested whether Celsr3 and Fzd3 could act via Isl1-positive guidepost cells. Isl1-positive cells appear in the forebrain at embryonic day (E) 9.5-E10.5 and, from E12.5, they form 2 contingents in ventral telencephalon and prethalamus. In control mice, corticothalamic axons run in the ventral telencephalic corridor in close contact with Isl1-positive cells. When Celsr3 or Fzd3 is inactivated in Isl1-expressing cells, corticofugal fibers stall and loop in the ventral telencephalic corridor of high Isl1 expression, and thalamic axons fail to cross the diencephalon-telencephalon junction (DTJ). At E12.5, before thalamic and cortical axons emerge, pioneer projections from Isl1-positive cells cross the DTJ from both sides in control but not mutant embryos. These early projections appear to act like a bridge to guide later growing thalamic axons through the DTJ. Our data suggest that Celsr3 and Fzd3 orchestrate the formation of a scaffold of pioneer neurons and their axons. This scaffold extends from prethalamus to ventral telencephalon and subcortex, and steers reciprocal corticothalamic fibers.

Keywords: Isl1; axon guidance; internal capsule; mouse; prethalamus.

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / metabolism
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • LIM-Homeodomain Proteins / genetics
  • LIM-Homeodomain Proteins / metabolism
  • Mice, Transgenic
  • Neuronal Outgrowth / physiology
  • RNA, Messenger / metabolism
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Thalamus / cytology
  • Thalamus / embryology*
  • Thalamus / metabolism
  • Tissue Culture Techniques
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Cadherins
  • Celsr3 protein, mouse
  • Dlx5 protein, mouse
  • Dlx6 protein, mouse
  • Frizzled Receptors
  • Fzd3 protein, mouse
  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • RNA, Messenger
  • RNA, Untranslated
  • Receptors, Cell Surface
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1