Computational Identification of Ligand-Receptor Pairs That Drive Human Astrocyte Development

Voss, Anna J.; Lanjewar, Samantha; Sampson, Maureen M.; King, Alexia; Hill, Emily; Sing, Anson; Sojka, Caitlin; Sloan, Steven A.

doi:10.2139/ssrn.4118998

Cited by 2 publications

(2 citation statements)

References 60 publications

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“…Conversely, increased mTORC1 signaling due to homozygous deletion of TSC1 or TSC2 enhances astroglial differentiation in 2D neural cultures and hBOs (Blair et al, 2018, Grabole et al, 2016, Costa et al, 2016). Recently, it has been shown that gliogenic factors may converge on mTOR signaling to drive astrogenesis in hBOs (Voss et al, 2023). However, the downstream pathways controlled by mTORC1 that regulate the gliogenic switch have not been defined.…”

Section: Introductionmentioning

confidence: 99%

STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity

Deb,

Li,

Blair

et al. 2023

Preprint

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During brain development, neural progenitor cells first produce neurons, then astrocytes and other glial cell types, which provide important trophic support and shape neuronal development and function. Intrinsic genetic programs interact with extracellular signals to control progenitor fate, resulting in temporally segregated periods of neurogenesis and gliogenesis. Animal models have implicated STAT3 as an important driver of astrogenesis; however, the signaling pathways that control glial differentiation during human brain development are less well understood. Prior work demonstrated that constitutive activation of mTORC1 signaling in human brain organoid models resulted in the precocious generation of glial-lineage cells. In this study, we tested whether mTORC1 acts via STAT3 to control astrogenesis in brain organoids. We show that knockdown of STAT3 reduces astrogenesis in wild-type organoids and in organoids with constitutively high mTORC1 signaling caused by deletion of the negative regulator TSC2. However, mTORC1 is not required for cytokine-induced activation of STAT3 and expression of the astrocytic protein GFAP. Together, these results show that mTORC1 acts through STAT3 to control astroglia production in human brain organoid models, but that mTOR signaling is dispensable for STAT3-driven astrogenesis.Summary statementDeb et al, use human brain organoid models to show a requirement for STAT3 downstream of mTORC1 in regulating astrogliogenesis during early human brain development.

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Section: Introductionmentioning

confidence: 99%

STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity

Deb,

Li,

Blair

et al. 2023

Preprint

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“…Very recently, Voss and colleagues demonstrated that the synergistic and combinatorial activity of five ligandreceptor pairs, driven by the ligands TGFβ2, NLGN1, TSLP, DKK1 and BMP4, guides astrogenesis in both human cortical organoids and primary fetal tissue. In this work, they additionally identified a time frame of effective responsivity to gliogenic signals, which corresponds to the initial postnatal developmental stages [29] (Figure 1). Thus, the tight regulation and coordination of all intracellular and extracellular stimuli along with cell-cell interactions implicated in controlling these events is critical for the establishment of a balanced ratio among all different cell types, their relative numbers, appropriate functional diversification, and correct formation of elaborated neuronal networks in each brain region [23].…”

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confidence: 98%

From Astrocyte Functions to Brain Dysfunctions: Brain “Stars” Take the Lead during Critical Periods of Early Postnatal Brain Development

Vivi,

Di Benedetto

2023

Preprint

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Astrocytes regulate the shape and functions of the synaptic and vascular compartments through modulatory membrane-bound proteins or released factors. Their peculiar position further allows them to form a functional unit that “senses” the brain state and secrete factors in the bloodstream as a reflection of this state. Imbalanced astrocyte activity can therefore have a drastic negative impact on the formation of neuronal synaptic networks and lead to the development of severe brain pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology and molecular make-up in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. The generation and differentiation/maturation of astrocytes (astrogenesis) occur during the critical period of early postnatal brain development. This is a time window of elevated astrocyte- and microglia-dependent synaptic phagocytosis (pruning), a process pivotal in refining neuronal networks. Therefore, any extrinsic and/or intrinsic cues altering this astrocyte-dependent synapse elimination during this critical period may result in altered synaptic remodeling and the onset of ND and NP disorders. Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodelling especially during early postnatal critical periods of brain development. We additionally propose alternative hypotheses to their putative involvement in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss sex-dependent effects on these neurodevelopmental processes.From a translational perspective, understanding age- and sex- dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease and may support the development of diagnostic tools or the selection of tailored treatment options for individual patients.

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Computational Identification of Ligand-Receptor Pairs That Drive Human Astrocyte Development

Cited by 2 publications

References 60 publications

STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity

STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity

From Astrocyte Functions to Brain Dysfunctions: Brain “Stars” Take the Lead during Critical Periods of Early Postnatal Brain Development

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