Fig. 2.

Developmental timelines for neurogenesis, gliogenesis, angiogenesis and barriergenesis in the brain and retina. (A,B) Developmental timelines (i) and schematic illustrations (ii) of the development of neurons, glial cells and blood vessels in the mouse cerebral cortex (A) and retina (B). (Ai) Neurogenesis in the cerebral cortex begins at E11, whereas gliogenesis starts at E13 (oligodendrocyte formation) and E18.5 (astrocyte formation). Neurogenesis is completed by P8-P10, whereas gliogenesis persists for prolonged periods in postnatal development corresponding to the expansion and maturation of astrocytes. Cortical angiogenesis also spans both the embryonic and postnatal stages of development, and is completed by P25. The initiation of BBB maturation [establishment of both paracellular (blue) and transcellular (pink) properties] starts soon after angiogenesis. However, by birth, both the paracellular and transcellular barrier properties of brain endothelial cells are mature. Dotted lines indicate the initiation and maturation of the endothelial barrier properties or the start of differentiation and appearance of mature astrocytes and oligodendrocytes. (Aii) Neurogenesis in the cortex occurs in an inside-out fashion (gray arrow), whereas angiogenesis occurs in an outside-in fashion (red arrow). Mature astrocytes ensheath blood vessels to ensure the maintenance of the BBB. (Bi) Amacrine cells, cones, ganglion cells and horizontal cells are born during the embryonic phase in the retina, whereas bipolar cells and Müller glia are born during the postnatal phase. Rod development occurs throughout both phases. Astrocytes migrate into the retina from E18.5 until P6. Growth of the superficial plexus (P1-P8) follows an astrocyte template, over the inner limiting membrane. Sprouts from the superficial vessels, guided by Müller glia, then form the deep (P8-P12) and intermediate (P12-P17) plexuses. The transcellular BRB matures by P10, whereas the paracellular barrier does not mature until P18. Upward arrows indicate the peak of development for each process. Dotted lines indicate the initiation and maturation of BRB properties in retinal endothelial cells. (Bii) Schematic diagram shows the relationship between distinct neuronal cell types and distinct vascular plexuses in the retina. Ganglion cell bodies reside in the ganglion cell layer, which is vascularized by the superficial plexus. Amacrine, bipolar, horizontal and Müller cell bodies reside in the inner nuclear layer, which is vascularized by the intermediate and deep vascular plexuses. Photoreceptors occupy the outer nuclear layer, which makes contacts with the deep vascular plexus.