Astrocyte development in the cerebral cortex: Complexity of their origin, genesis, and maturation

Abstract

In the mammalian brain, astrocytes form a heterogeneous population at the morphological, molecular, functional, intra-, and inter-region levels. In the past, a few types of astrocytes have been first described based on their morphology and, thereafter, according to limited key molecular markers. With the advent of bulk and single-cell transcriptomics, the diversity of astrocytes is now progressively deciphered and its extent better appreciated. However, the origin of this diversity remains unresolved, even though many recent studies unraveled the specificities of astroglial development at both population and individual cell levels, particularly in the cerebral cortex. Despite the lack of specific markers for each astrocyte subtype, a better understanding of the cellular and molecular events underlying cortical astrocyte diversity is nevertheless within our reach thanks to the development of intersectional lineage tracing, microdissection, spatial mapping, and single-cell transcriptomic tools. Here we present a brief overview describing recent findings on the genesis and maturation of astrocytes and their key regulators during cerebral cortex development. All these studies have considerably advanced our knowledge of cortical astrogliogenesis, which relies on a more complex mode of development than their neuronal counterparts, that undeniably impact astrocyte diversity in the cerebral cortex.

Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex

“…When we characterized Ptprd expression in this novel mouse model, we observed that transcripts were reduced by more than half at E16.5 ( Figure 1B ) when gliogenesis started. At this embryonic stage, some cells derived from dorsal structures are expected to have migrated to the forebrain ( Gorski et al, 2002 ; Clavreul et al, 2019 ; Shen et al, 2021 ; Clavreul et al, 2022 ), which explains why Ptprd expression is not fully abolished in the PTPRD cKO mouse cortex. Moreover, we cultured E16.5 cortical NPCs as neurospheres and measured Ptprd expression after 7 DIV ( Figure 1C ), finding that forebrain NPCs derived from PTPRD cKO embryos lacks Ptprd expression.…”

“…Additional results showed decreased astrocytes and oligodendrocytes in the PTPRD cKO postnatal cortex, which correlates with reduced myelin expression in the corpus callosum. Since most perinatal cortical astrocytes and their precursors originate from cortical NPCs and astrocyte local proliferation ( Tsai et al, 2012 ; Clavreul et al, 2019 ; Vogel and Wegner, 2021 ; Clavreul et al, 2022 ), the reduced number of radial glia cells (Pax6+) and astrocytic progenitors (Sox9+) ( Kang et al, 2012 ; Martini et al, 2013 ; Sloan and Barres, 2014 ), and the postnatal reduction of GFAP+ astrocytes observed in PTPRD cKO mouse cortex indicates that PTPRD has a role in astrogliogenesis. This observation can also be extended to oligodendrogenesis since most OPCs and oligodendrocytes originated from EMX1+ NPCs are in the main areas studied here, such as deep cortical layers and white matter ( Shen et al, 2021 ), suggesting that PTPRD would also regulate oligodendrogenesis.…”

“…This impaired developmental gliogenesis could have profound implications in the adult brain since after P7, cortical astrocytes do not proliferate locally ( Clavreul et al, 2019 ), leading to several disruptions in brain function, such as neurotransmitter imbalances, impaired synaptic function, disrupted brain circuits, and worsen neuronal physiology ( Clavreul et al, 2022 ). As for oligodendrocytes, since OPCs are the most proliferative cells in the brain and maintain their stemness until adulthood ( Goldman and Kuypers, 2015 ), further research is needed to determine if the absence of PTPRD in cortical NPCs produces a reduced oligodendrogenesis that is sustained over time, or if it only delays it as has been seen in the spinal cord ( Zhu et al, 2015 ).…”

Astrocytic thrombospondins 1 and 2 are required for cortical synapse development controlling instrumental performance

“…The ablation of TSP1/2 in adult astrocytes did not alter performance during operant tasks. However, when we ablated TSP1/2 in neonatal astrocytes, targeting a period corresponding to the start of astrocyte morphogenesis, synapse development, and normal expression of TSP1/2 in the cortex [106,107], we found a significant decrease in performance during high-effort tasks. This is consistent with previous findings in the literature showing that cortical astrocytes express TSP1/2 within the first two weeks of post-natal development, but the expression is diminished by P21 [29].…”

High-resolution 3D ultrastructural analysis of developing mouse neocortex reveals long slender processes of endothelial cells that enter neural cells

“…The neurons thus generated delaminate from the VZ and migrate, through the intermediate zone (IZ), to the cortical plate (CP) ( Cardenas et al, 2018 ; Cardenas and Borrell, 2020 ). The newborn BPs also delaminate from the VZ but migrate only to the SVZ, where, depending on the mammalian species, they undergo a varying degree of self-amplification, followed by the generation of neurons and later of macroglial cells (astrocytes and oligodendrocytes; a process called gliogenesis) ( Kriegstein and Alvarez-Buylla, 2009 ; Taverna et al, 2014 ; Tabata, 2015 ; Ohtsuka and Kageyama, 2019 ; Clavreul et al, 2022 ).…”