Abstract
The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. We uncover long-range regulation of this process originating at the telencephalic dorsal midline, where levels of secreted Bmps are maintained by factors in both the neuroepithelium and the overlying mesenchyme. In the mouse, the combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. This alters the spatial and temporal Wnt signaling profile of the dorsal midline cortical hem, which in turn causes gyrification of the distal neocortex. Our study uncovers early mesenchymal-neuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling.
Highlights
The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood
Recent studies have revealed a coordinated sequence of neurogenic events in the developing neocortex of naturally gyrencephalic mammals, which begins with an early accumulation of apical cortical progenitors (APs) in the neocortical ventricular zone (VZ), followed by expansion of basal progenitors (BPs), including intermediate progenitors (IPs) and basal radial glia
We show that simultaneous loss of two transcription factors, Lmx1a, expressed in the telencephalic dorsal midline neuroepithelium (DMe), and Lmx1b, expressed in head mesenchyme, causes folding of the mouse cerebral cortex, implicating head mesenchyme and DMe in the regulation of cortical gyrification
Summary
The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. The combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. Our study uncovers early mesenchymalneuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling. Dual loss of the adhesion genes Flrt[1] and Flrt[3] affects migration of differentiating neurons and results in folding of the mouse neocortex In this mouse model, cortical folding develops without the predominant expansion of BPs observed in higher mammals[25]. Our study identifies an unexpected role of dorsal midline signaling in the long-range regulation of cortical gyrification and shows that mesenchymal–neuroepithelial interactions are necessary to maintain lissencephaly in mice
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