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Sonic hedgehog expands neural stem cells in the neocortical region leading to an expanded and wrinkled neocortical surface

MOHAMMED, J.M. SHQIRAT 京都大学 DOI:10.14989/doctor.k23464

2021.09.24

概要

The cerebral neocortex, a six-layered folded structure, is the hallmark of complex motor, sensory and cognitive functions. Higher mammals, including humans, possess the neocortex with complicated wrinkles, whereas other species have a smooth, less developed neocortex. Sonic hedgehog (Shh), a key morphogen, is expressed in the floor plate of the developing neural tube and plays a key role in establishing the dorso-ventral (D-V) axis. Increasing evidence has revealed that Shh promotes cell proliferation of various types of neural cells. However, there have been few studies that demonstrated the impact of Shh on neocortical neural stem cells (NSCs) and progenitors in the developing brain.

To investigate the effect of Shh on neocortical development, firstly, in utero electroporatio n experiments was performed, using Shh expression vectors and observed that transient overexpression of Shh led to an increase in Pax6+ NSCs and Tbr2+ intermediate progenitor cells (IPCs) in the lateral ventricles by promoting cell proliferation. Furthermo re, the observation of NSCs transfected with Shh expression vectors continued symmetric proliferative divisions.

To analyze the effect of Shh on neocortical development more in detail, a transgenic (Tg) mice were generated ,using the Tet-on system, in which Shh and d2EGFP are co-expressed in NSCs and neural progenitors under the control of the nestin promoter. The Shh-overexpressing Tg mice exhibited a bigger brain size, a dramatic expansion of lateral ventricles, a tangential extension of the VZ/SVZ of the neocortical region, and the formation of wrinkles on the neocortical surface. BrdU incorporation experiments and immunostaining with Ki67 revealed the promoted cell proliferation in the VZ/SVZ of the Tg brain. Pax6+ NSCs were increased in the VZ/SVZ at the expense of Tbr2+ IPCs, indicating that neuronal differentiation was suppressed in the neocortical region of Tg mice. In addition, the observation of many of NSCs continued symmetric proliferative divisions in th e Tg brain. Based on the observation that Shh-expressing cells were sparsely distributed in the VZ/SVZ of the Tg brain, these results suggested that Shh secreted from a fraction of VZ/SVZ cells exerted the non-cell autonomous effect on NSCs in broad areas of the neocortical region. Upregulation of Gli1 in the VZ/SVZ in broad areas of the Tg brain corroborated the suggestion that Shh proteins were widely distributed and caused the activation of Shh signaling in broad areas, thus expanding NSCs by a non-cell autonomous effect.

In addition, it was found that the expression level of Hes1 was significantly upregulated and that of Neurog2 was reduced in the neocortical region of the Shh-overexpressing Tg brain, suggesting that the upregulation of Hes1 led to the inhibition of neuronal differentiation by repressing or counteracting Neurog2 and maintained the proliferation of NSCs in the neocortical region of Tg mice. for further examination, whether Shh overexpression exerted a ventralization effect on the developing telencephalon by analyzing the expression patterns and levels of several D-V marker genes, and observed that some ventral marker genes such as Ascl1, Dlx1 and Gad1 were ectopically upregulated in the dorsal telencephalon of Tg mice. However, regardless of the upregulation of these genes, the neocortical layer structure was not severely disturbed in the postnatal Tg brain. These results indicated that NSCs in the neocortical region of Tg mice were capable of producing cortical layer neuron s and formed orderly cortical layers, without inducing a drastic disturbance in D-V patterning.
In conclusion, our Tg system enabled control of the timing and levels of Shh expression by modulating the doxycycline dosage in drinking water, and thus succeeded in the acquisition of a prominently enlarged neocortica l surface with complicated wrinkles and folds. These results suggested that enhanced activation of Shh signaling during neocortical development might have contributed to mammalian brain evolution.

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