Abstract
BackgroundAgenesis 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.ResultsOur 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.ConclusionThe 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.
Highlights
Agenesis of the corpus callosum is associated with many human developmental syndromes
We demonstrate that, at embryonic day 18 (E18), a small population of axons does cross the midline caudally in Nfib-deficient mice. These results demonstrate that Nfib is critical for the maturation of midline glia that are required for corpus callosum (CC) formation
NFIB is expressed at the cortical midline we previously showed by retrograde labelling that NFIB was not highly expressed in neocortical callosal neurons [23], we wanted to examine what other cells expressed NFIB at the midline
Summary
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. Formation of the CC requires a series of dynamic events to be co-ordinated both spatially and temporally during both embryogenesis and the postnatal period. These include correct patterning of the midline, differentiation and specification of callosal neurons within the nascent cortical plate, the development of distinct midline glial populations, targeting of axons to the contralateral hemisphere and the elimination of those supernumerary axons overproduced during development [1,4]. While the clinical significance of the CC has long been known, our understanding of the molecular determinants underlying formation of this fibre tract remains incomplete
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