Specification and morphogenesis of astrocytes

Abstract

Astrocytes are the most abundant cell type in the mammalian brain. Interest in astrocyte function has increased dramatically in recent years because of their newly discovered roles in synapse formation, maturation, efficacy, and plasticity. However, our understanding of astrocyte development has lagged behind that of other brain cell types. We do not know the molecular mechanism by which astrocytes are specified, how they grow to assume their complex morphologies, and how they interact with and sculpt developing neuronal circuits. Recent work has provided a basic understanding of how intrinsic and extrinsic mechanisms govern the production of astrocytes from precursor cells and the generation of astrocyte diversity. Moreover, new studies of astrocyte morphology have revealed that mature astrocytes are extraordinarily complex, interact with many thousands of synapses, and tile with other astrocytes to occupy unique spatial domains in the brain. A major challenge for the field is to understand how astrocytes talk to each other, and to neurons, during development to establish appropriate astrocytic and neuronal network architectures.

Fig. 1

Intrinsic epigenetic mechanisms converge with extrinsic signals to promote astrocyte fate from NPCs. (A) In early NPCs, chromatin is open at the neurogenin1 and neurogenin2 (ngn1 and 2) loci, Wnt signals can activate their expression, and neurogenins promote neuronal fate and inhibit astrocyte fate. In postnatal NPCs, the ngn1 and 2 loci have been methylated and bound by PcG, chromatin is closed, Wnt-dependent ngn1 and 2 expression is suppressed, and astrocyte fate is in turn derepressed. (B) Astrocyte genes are methylated during embryonic stages, which closes local chromatin; this is maintained by DNMT1, and astrocyte fate is suppressed, despite the presence of low levels of the proastrocyte factor CT-1. At the switch from NPC production of neurons to astrocytes, Ngn⁺ neurons release additional CT-1, which activates JAK-STAT signaling, and also activates Notch signaling (likely through JAG1 or DLL2), which activates NFIA, an inhibitor of Dnmt1 activity. Positive JAK-STAT signaling, coupled with opening of chromatin at astrocyte gene loci, promotes astrocyte fate.

Fig. 2

Astrocyte diversity is generated by production from unique spatial domains. (A) A schematic illustrating VA1, VA2, and VA3 domains of the spinal cord white matter astrocytes and expression domains of Reelin and Slit1. (B) A homeodomain code that controls the generation of neuronal diversity is reused during astrocyte specification to promote white matter astrocyte diversity. [(A) and (B) are adapted from (12)]

Fig. 3

Astrocyte morphology is far more complex than initially appreciated. Astrocytes in an organotypic slice preparation labeled with the common marker GFAP (red) overlaid with a single astrocyte transfected with the membrane marker Lck-GFP (green fluorescent protein). Arrow indicates GFAP label of Lck-GFP–marked astrocyte. [From (53) with permission from Elsevier]

Fig. 4

Coordination of astrocyte morphological growth and refinement with synapse formation. (A) Although most neurons are made during embryonic stages, the major waves of synaptogenesis follow and depend on astrocyte production. The timing of astrocyte growth and morphological refinement overlaps significantly with this window of synaptogenesis. (B) Astrocytes initially extend large, filopodial processes that overlap significantly with neighboring astrocytes; however, by postnatal day 21, astrocytes refine their morphology to occupy unique spatial domains and elaborate fine processes that closely associate with synapses. (C) A complex interrelation exists between synapses and astrocyte processes. Eph or ephrin signaling can bidirectionally control astrocyte features, as well as spine morphology (see text).