Oriented Cell Divisions Induce Basal Progenitors and Regulate Neural Expansion Across Tissues and Species
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE312067 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:A fundamental role for division orientation in progenitor output driving cortical and retinal growth is revealed.
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Project description:Oriented Cell Divisions Induce Basal Progenitors and Regulate Neural Expansion Across Tissues and Species
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Project description:Mitotic spindle orientation is crucial for cell fate determination and tissue organization. Although the intracellular machinery governing spindle orientation is well characterized, whether and how secreted factors, such as morphogens, regulate this process remains poorly understood. This study investigated the role of Hedgehog (HH) signaling in modulating mitotic spindle orientation in neural progenitor cells and in induced pluripotent stem cells (iPSCs). Time-lapse microscopy of cerebral organoids and iPSCs revealed that HH signaling increases the angle of the mitotic spindle relative to the apical surface, prolongs mitosis, and enhances spindle rotation. Mechanistically, HH signaling reduces both the number and the length of astral microtubules, key regulators of spindle orientation. This reduction correlates with increased spindle angle in iPSCs. Furthermore, we show that canonical HH signaling, involving GLI-dependent transcriptional regulation, contributes to these effects. RNA sequencing and gene set enrichment analysis (GSEA) revealed that HH signaling upregulates genes associated with microtubule depolymerization, suggesting a transcriptional mechanism by which HH signaling influences astral microtubule dynamics and, consequently, mitotic spindle orientation. These findings highlight a novel link between a morphogen, transcriptional regulation, and the control of mitotic spindle orientation, with implications for development and tissue homeostasis.
2025-06-25 | GSE296672 | GEO
Project description:Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution.
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Project description:In multicellular organisms, the execution of developmental and homeostatic programs often rely on asymmetric cell divisions. These divisions require the alignment of the mitotic spindle axis to cortical polarity cues, and the unequal partitioning of cellular components between progeny cells. Asymmetric divisions are orchestrated by niche signals frequently presented in a directional manner, such as Wnt signals. Here we employ bioengineered Wnt-niches to demonstrate that in metaphase NuMA/dynein microtubule motors form a complex with Lrp6 and -catenin at the cortical sites of Wnt activation to orient cell division perpendicularly. We show that engagement of Lrp6 receptors by Wnt ligands locally stabilizes actomyosin contractility through the accumulation of myosin-1c. Additionally, we developed a proteomic-based approach to identify mitotic protein networks enriched at the Wnt-contact site, revealing that mitochondria polarize toward localized Wnt sources and are asymmetrically partitioned to the Wnt-proximal daughter cell during Wnt-mediated asymmetric cell division of embryonic stem cells. Our findings enhance the understanding of mitotic Wnt-signaling, and elucidate fundamental principles underlying Wnt-dependent cell polarization.
2025-12-08 | PXD069774 | Pride
Project description:Correct chromosome segregation during cell division depends on proper connections between spindle microtubules and kinetochores. During prometaphase, kinetochores are temporarily covered with a dense protein meshwork known as the fibrous corona. Formed by oligomerization of ROD/ZW10/ZWILCH-SPINDLY (RZZ-S) complexes, the fibrous corona promotes spindle assembly, chromosome orientation and spindle checkpoint signaling. The molecular requirements for formation of the fibrous corona are not fully understood. Here we show that the fibrous corona depends on the mitotic kinesin CENP-E, and that poorly expanded fibrous coronas after CENP-E depletion are functionally compromised. This previously unrecognized role for CENP-E does not require its motor activity but instead is driven by its C-terminal microtubule-binding region and farnesyl modification thereof. The ‘birth’ of a farnesylation motif in CENP-E orthologs during Obazoa evolution closely aligns with presence of the full RZZ-S module, and we show that in cells CENP-E interacts with RZZ-S complexes in a farnesyl-dependent manner. CENP-E is recruited to kinetochores following RZZ-S, and - while not required for RZZ-S oligomerization per se - promotes subsequent fibrous corona expansion. Our results show that proper spindle assembly has a non-motor contribution from the kinesin CENP-E through stabilization of the fibrous corona meshwork during its formation.
2023-10-09 | PXD040338 | Pride
Project description:Identify gene expression changes in the absence of Plk2 Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Comparison between Plk2 +/+ (n=3) and Plk2 -/- (n=3) mouse mammary epithelial cells
2014-05-20 | E-GEOD-50003 | biostudies-arrayexpress
Project description:Identify gene expression changes in the absence of Plk2 Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis. Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and is a putative tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development and as a tumor suppressor in mammary tumorigenesis.
2014-05-20 | GSE50003 | GEO
Project description:Formation of correctly shaped organs is vital for normal function. The Drosophila wing has an elongated shape, which has been attributed in part to a preferential orientation of mitotic spindles along the proximal-distal axis [1, 2]. Orientation of mitotic spindles is believed to be a fundamental morphogenetic mechanism in multicellular organisms [3-6]. A contribution of spindle orientation to wing shape was inferred from observations that mutation of Dachsous-Fat pathway genes results in both rounder wings and loss of the normal proximal-distal bias in spindle orientation [1, 2, 7]. To directly evaluate the potential contribution of spindle orientation to wing morphogenesis, we assessed the consequences of loss of the Drosophila NuMA homolog Mud, which interacts with the dynein complex and has a conserved role in spindle orientation [8, 9]. Loss of Mud randomizes spindle orientation but does not alter wing shape. Analysis of growth and cell dynamics in developing discs and in ex vivo culture suggests that the absence of oriented cell divisions is compensated for by an increased contribution of cell rearrangements to wing shape. Our results indicate that oriented cell divisions are not required for wing morphogenesis, nor are they required for the morphogenesis of other Drosophila appendages. Moreover, our results suggest that normal organ shape is not achieved through locally specifying and then summing up individual cell behaviors, like oriented cell division. Instead, wing shape might be specified through tissue-wide stresses that dictate an overall arrangement of cells without specifying the individual cell behaviors needed to achieve it.
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Project description:How control of subcellular events in single cells determines morphogenesis on the scale of the tissue is largely unresolved. The stereotyped cross-midline mitoses of progenitors in the zebrafish neural keel provide a unique experimental paradigm for defining the role and control of single-cell orientation for tissue-level morphogenesis in vivo. We show here that the coordinated orientation of individual progenitor cell division in the neural keel is the cellular determinant required for morphogenesis into a neural tube epithelium with a single straight lumen. We find that Scribble is required for oriented cell division and that its function in this process is independent of canonical apicobasal and planar polarity pathways. We identify a role for Scribble in controlling clustering of α-catenin foci in dividing progenitors. Loss of either Scrib or N-cadherin results in abnormally oriented mitoses, reduced cross-midline cell divisions, and similar neural tube defects. We propose that Scribble-dependent nascent cell-cell adhesion clusters between neuroepithelial progenitors contribute to define orientation of their cell division. Finally, our data demonstrate that while oriented mitoses of individual cells determine neural tube architecture, the tissue can in turn feed back on its constituent cells to define their polarization and cell division orientation to ensure robust tissue morphogenesis.
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