Caspr Controls the Temporal Specification of Neural Progenitor Cells through Notch Signaling in the Developing Mouse Cerebral Cortex

The generation of layer-specific neurons and astrocytes by radial glial cells during development of the cerebral cortex follows a precise temporal sequence, which is regulated by intrinsic and extrinsic factors. The molecular mechanisms controlling the timely generation of layer-specific neurons and astrocytes remain not fully understood. In this study, we show that the adhesion molecule contactin-associated protein (Caspr), which is involved in the maintenance of the polarized domains of myelinated axons, is essential for the timing of generation of neurons and astrocytes in the developing mouse cerebral cortex. Caspr is expressed by radial glial cells, which are neural progenitor cells that generate both neurons and astrocytes. Absence of Caspr in neural progenitor cells delays the production cortical neurons and induces precocious formation of cortical astrocytes, without affecting the numbers of progenitor cells. At the molecular level, Caspr cooperates with the intracellular domain of Notch to repress transcription of the Notch effector Hes1. Suppression of Notch signaling via a Hes1 shRNA rescues the abnormal neurogenesis and astrogenesis in Caspr-deficient mice. These findings establish Caspr as a novel key regulator that controls the temporal specification of cell fate in radial glial cells of the developing cerebral cortex through Notch signaling.