title: Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice.
abstract: BACKGROUND
  Agenesis of the corpus callosum is associated with many human developmental syndromes. Key mechanisms regulating callosal formation include the guidance of axons arising from pioneering neurons in the cingulate cortex and the development of cortical midline glial populations, but their molecular regulation remains poorly characterised. Recent data have shown that mice lacking the transcription factor Nfib exhibit callosal agenesis, yet neocortical callosal neurons express only low levels of Nfib. Therefore, we investigate here how Nfib functions to regulate non-cell-autonomous mechanisms of callosal formation.
  
  
  RESULTS
  Our investigations confirmed a reduction in glial cells at the midline in Nfib-/- mice. To determine how this occurs, we examined radial progenitors at the cortical midline and found that they were specified correctly in Nfib mutant mice, but did not differentiate into mature glia. Cellular proliferation and apoptosis occurred normally at the midline of Nfib mutant mice, indicating that the decrease in midline glia observed was due to deficits in differentiation rather than proliferation or apoptosis. Next we investigated the development of callosal pioneering axons in Nfib-/- mice. Using retrograde tracer labelling, we found that Nfib is expressed in cingulate neurons and hence may regulate their development. In Nfib-/- mice, neuropilin 1-positive axons fail to cross the midline and expression of neuropilin 1 is diminished. Tract tracing and immunohistochemistry further revealed that, in late gestation, a minor population of neocortical axons does cross the midline in Nfib mutants on a C57Bl/6J background, forming a rudimentary corpus callosum. Finally, the development of other forebrain commissures in Nfib-deficient mice is also aberrant.
  
  
  CONCLUSIONS
  The formation of the corpus callosum is severely delayed in the absence of Nfib, despite Nfib not being highly expressed in neocortical callosal neurons. Our results indicate that in addition to regulating the development of midline glial populations, Nfib also regulates the expression of neuropilin 1 within the cingulate cortex. Collectively, these data indicate that defects in midline glia and cingulate cortex neurons are associated with the callosal dysgenesis seen in Nfib-deficient mice, and provide insight into how the development of these cellular populations is controlled at a molecular level.
authors: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. m.piper@uq.edu.au
authors: Michael
authors: M
authors: Piper
authors: Randal X
authors: RX
authors: Moldrich
authors: Charlotta
authors: C
authors: Lindwall
authors: Erica
authors: E
authors: Little
authors: Guy
authors: G
authors: Barry
authors: Sharon
authors: S
authors: Mason
authors: Nana
authors: N
authors: Sunn
authors: Nyoman Dana
authors: ND
authors: Kurniawan
authors: Richard M
authors: RM
authors: Gronostajski
authors: Linda J
authors: LJ
authors: Richards
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D003337:Corpus Callosum / Q000196:embryology* / Q000503:physiopathology*; D006179:Gyrus Cinguli / Q000196:embryology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019579:Neocortex / Q000196:embryology* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D039942:Neuropilin-1 / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology / Q000503:physiopathology; D013234:Stem Cells / Q000502:physiology; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051839:NFI Transcription Factors; D009419:Nerve Tissue Proteins; C484683:Nfib protein, mouse; D039942:Neuropilin-1; D000098552:Slit Homolog 2 Protein