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Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.

ABSTRACT: Symmetric and asymmetric cell divisions are conserved strategies for stem cell expansion and the generation of more committed progeny, respectively. Here, we demonstrate that in human neural stem cells (NSCs), lysosomes are asymmetrically inherited during mitosis. We show that lysosomes contain Notch receptors and that Notch activation occurs the acidic lysosome environment. The lysosome asymmetry correlates with the expression of the Notch target gene HES1 and the activity of Notch signaling in the daughter cells. Furthermore, an asymmetry of lysosomes and Notch receptors was also observed in a human organoid model of brain development with mitotic figures showing preferential inheritance of lysosomes and Notch receptor in that daughter cell remaining attached to the apical membrane. Thus, this study suggests a previously unknown function of lysosomes as a signaling hub to establish a bias in Notch signaling activity between daughter cells after an asymmetric cell division of human NSCs.

SUBMITTER: Bohl B

PROVIDER: S-EPMC8836802 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.

Bohl Bettina B Jabali Ammar A Ladewig Julia J Koch Philipp P

Science advances 20220211 6

Symmetric and asymmetric cell divisions are conserved strategies for stem cell expansion and the generation of more committed progeny, respectively. Here, we demonstrate that in human neural stem cells (NSCs), lysosomes are asymmetrically inherited during mitosis. We show that lysosomes contain Notch receptors and that Notch activation occurs the acidic lysosome environment. The lysosome asymmetry correlates with the expression of the Notch target gene <i>HES1</i> and the activity of Notch signa ...[more]

PMID: 35148180

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Project description:The human brain formation involves complicated processing, which is regulated by a gene regulatory network influenced by different signaling pathways. The cross-regulatory interactions between elements of different pathways affect the process of cell fate assignment during neural and astroglial tissue patterning. In this study, the interactions between Wnt and Notch pathways, the two major pathways that influence neural and astroglial differentiation of human induced pluripotent stem cells (hiPSCs) individually, were investigated. In particular, the synergistic effects of Wnt-Notch pathway on the neural patterning processes along the anterior-posterior or dorsal-ventral axis of hiPSC-derived cortical spheroids were explored. The human cortical spheroids derived from hiPSCs were treated with Wnt activator CHIR99021 (CHIR), Wnt inhibitor IWP4, and Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester [DAPT]) individually, or in combinations (CHIR + DAPT, IWP4 + DAPT). The results suggest that CHIR + DAPT can promote Notch signaling, similar or higher than CHIR alone, whereas IWP4 + DAPT reduces Notch activity compared to IWP4 alone. Also, CHIR + DAPT promoted hindbrain marker HOXB4 expression more consistently than CHIR alone, while IWP4 + DAPT promoted Olig2 expression, indicating the synergistic effects distinctly different from that of the individual small molecule. In addition, IWP4 simultaneously promoted dorsal and ventral identity. The patterned neural spheroids can be switched for astroglial differentiation using bone morphogenetic protein 4. This study should advance the derivations of neurons, astroglial cells, and brain region-specific organoids from hiPSCs for disease modeling, drug screening, as well as for hiPSC-based therapies. Impact Statement Wnt signaling plays a central role in neural patterning of human pluripotent stem cells. It can interact with Notch signaling in defining dorsal-ventral and rostral-caudal (or anterior-posterior) axis of brain organoids. This study investigates novel Wnt and Notch interactions (i.e., Wntch) in neural patterning of dorsal forebrain spheroids or organoids derived from human induced pluripotent stem cells. The synergistic effects of Wnt activator or inhibitor with Notch inhibitor were observed. This study should advance the derivations of neurons, astroglial cells, and brain region-specific organoids from human stem cells for disease modeling and drug screening, as well as for stem cell-based therapies. The results can be used to establish better in vitro culture methods for efficiently mimicking in vivo structure of central nervous system.

Project description:During asymmetric stem cell division, polarization of the cell cortex targets fate determinants unequally into the sibling daughters, leading to regeneration of a stem cell and production of a progenitor cell with restricted developmental potential. In mitotic neural stem cells (neuroblasts) in fly larval brains, the antagonistic interaction between the polarity proteins Lethal (2) giant larvae (Lgl) and atypical Protein Kinase C (aPKC) ensures self-renewal of a daughter neuroblast and generation of a progenitor cell by regulating asymmetric segregation of fate determinants. In the absence of lgl function, elevated cortical aPKC kinase activity perturbs unequal partitioning of the fate determinants including Numb and induces supernumerary neuroblasts in larval brains. However, whether increased aPKC function triggers formation of excess neuroblasts by inactivating Numb remains controversial. To investigate how increased cortical aPKC function induces formation of excess neuroblasts, we analyzed the fate of cells in neuroblast lineage clones in lgl mutant brains. Surprisingly, our analyses revealed that neuroblasts in lgl mutant brains undergo asymmetric division to produce progenitor cells, which then revert back into neuroblasts. In lgl mutant brains, Numb remained localized in the cortex of mitotic neuroblasts and failed to segregate exclusively into the progenitor cell following completion of asymmetric division. These results led us to propose that elevated aPKC function in the cortex of mitotic neuroblasts reduces the function of Numb in the future progenitor cells. We identified that the acyl-CoA binding domain containing 3 protein (ACBD3) binding region is essential for asymmetric segregation of Numb in mitotic neuroblasts and suppression of the supernumerary neuroblast phenotype induced by increased aPKC function. The ACBD3 binding region of Numb harbors two aPKC phosphorylation sites, serines 48 and 52. Surprisingly, while the phosphorylation status at these two sites directly impinged on asymmetric segregation of Numb in mitotic neuroblasts, both the phosphomimetic and non-phosphorylatable forms of Numb suppressed formation of excess neuroblasts triggered by increased cortical aPKC function. Thus, we propose that precise regulation of cortical aPKC kinase activity distinguishes the sibling cell identity in part by ensuring asymmetric partitioning of Numb into the future progenitor cell where Numb maintains restricted potential independently of regulation by aPKC.

Dataset Information

Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.

Publications

Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.

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