TY - JOUR
T1 - Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice
AU - Piper, Michael
AU - Moldrich, Randal X.
AU - Lindwall, Charlotta
AU - Little, Erica
AU - Barry, Guy
AU - Mason, Sharon
AU - Sunn, Nana
AU - Kurniawan, Nyoman Dana
AU - Gronostajski, Richard M.
AU - Richards, Linda J.
N1 - Funding Information:
We thank John Baisden, Oressia Zalucki, Jane Ellis and the UQBR Animal Facility for technical assistance, Marc Tessier-Lavigne (Genentech) for the Slit2 riboprobe and Robert Hevner (University of Washington), Helen Cooper (Queensland Brain Institute), Giorgio Corte (University of Genova Medical School) and Niels Danbolt (University of Oslo) for reagents. The 16.4T facility is part of the Queensland NMR network, funded by the Queensland Government Smart State initiative. This work was funded by a National Health and Medical Research Council project grant (LJR) and a Clive and Vera Ramaciotti grant (MP). The following authors were supported by National Health and Medical Research Council fellowships: LJR (Senior Research Fellowship); MP (Howard Florey Centenary Fellowship and Biomedical Career Development Award); RXM (CJ Martin Fellowship). SM is supported by a University of Queensland F.G Meade PhD Scholarship. NDK is grateful for the support of Lembaga Eijkman, Jakarta.
PY - 2009
Y1 - 2009
N2 - 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. Conclusion. 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.
AB - 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. Conclusion. 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.
UR - http://www.scopus.com/inward/record.url?scp=74549130508&partnerID=8YFLogxK
U2 - 10.1186/1749-8104-4-43
DO - 10.1186/1749-8104-4-43
M3 - Article
C2 - 19961580
AN - SCOPUS:74549130508
SN - 1749-8104
VL - 4
JO - Neural Development
JF - Neural Development
IS - 1
M1 - 43
ER -