Astrocyte development and heterogeneity

Abstract

Astrocytes have many roles within the brain parenchyma, and a subpopulation restricted to germinal niches functions as neural stem cells (NSCs) that produce various types of neuronal progeny in relation to spatiotemporal factors. A growing body of evidence supports the concept of morphological and molecular differences between astrocytes in different brain regions, which might relate to their derivation from regionally patterned radial glia. Indeed, the notion that astrocytes are molecularly and functionally heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information into adulthood. Here, we discuss recent evidence for regionally encoded functions of astrocytes in the developing and adult CNS to provide an integrated concept of the origin and possible function of astrocyte heterogeneity. We focus on the regionalization of NSCs in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain and emerging evidence for a segmental organization of astrocytes in the developing spinal cord and forebrain. We propose that astrocytes' diversity will provide fundamental clues to understand regional brain organization and function.

Figure 1.

Developmental origins of adult parenchymal and V-SVZ astrocyte heterogeneity. (A) The regional specification of neuroepithelial (NE) cells, (B) radial glia (RG), and (C) V-SVZ and parenchymal astrocytes (D) throughout development. NE and RG cells at different regions of the developing forebrain (A and B), including the pallium (green), the lateral and medial ganglionic eminences (LGE and MGE in blue and orange, respectively), and septum (purple), give rise to adult V-SVZ NSCs at the different walls of the lateral ventricles and parenchymal astrocytes that maintain key positional information cues to control the progeny they produce and function, respectively. (D) Neural stem cell lineage progression during brain development. NE gives rise to neurogenic RG that generate different neuronal subtypes in a sequential manner. At later stages of embryogenesis, neurogenic RG become gliogenic to produce astrocytes. Whether RG sequentially generate different astrocyte subtypes remains to be determined. The final location of astrocytes in restricted spatial domains is determined by a DV segmental template. RG also give rise to V-SVZ astrocytes that produce different subtypes of OB interneurons depending on the region in which they are located. OB, olfactory bulb; V–SVZ, ventricular–subventricular zone.

Figure 2.

Models of intrinsic versus neuron-induced specification of regional astrocyte heterogeneity in the spinal cord. (A) Embryonic patterning along the DV axis gives rise to regionally specified RG. Signaling by Shh and BMPs regulate the expression of segmental transcription factors, and cross-repressive interactions refine progenitor domains. After neurogenesis, astrocytes are generated in all domains of the spinal cord. They migrate laterally along the RG trajectories and do not undergo tangential migration from their domains of origin. (B) Embryonic patterning specifies regionally distinct astrocytes. The segmental code established during early patterning could be used during gliogenesis to specify segmental astrocyte subtypes and determines the spatial allocation of astrocytes. (C) Extrinsic cues from local neurons might also determine regional astrocyte features (motor neurons are depicted). (D) Segmental heterogeneity of fibrous and protoplasmic astrocytes could give rise to astromeres (i.e., astrocyte domains with distinct functions). This is a speculative concept and an area for future research. BMP, bone morphogenetic protein; SCL, stem cell leukemia; VZ, ventricular zone.