Biology subjects

Cheong, I.

Publications and source records attributed to Cheong, I..

5 recordsLinked to original sources

bioRxiv2026

Integration of human and mouse single-cell transcriptomes of the developing cerebellum nominates cells-of-origin for Group 3 and 4 medulloblastoma

The cerebellar rhombic lip neurogenic niche is critical for glutamatergic neurogenesis, and dysregulated differentiation of rhombic lip lineage cells is hypothesized to cause medulloblastoma (MB), a malignant pediatric cancer lacking targeted therapies. Humans have an expanded rhombic lip subventricular zone compartment not seen in mice or macaques, and the common Group 4 subtype of MB is hypothesized to arise by dysregulation of the EOMES+ unipolar brush cells (UBC) generated by this compartment. However, it is unknown whether humans have unique UBC populations not seen in the mouse and, if so, whether Group 4 MB tumour cells resemble these UBC populations. We integrated 336,598 human and mouse single-cell transcriptomes of the developing cerebellum (9-21 post-conception weeks in humans and E10-P14 in mice) and identified two subpopulations of UBC that are enriched in the human samples, relative to mice. One of these populations, which we term UBC 1, predominates at 11 post-conception weeks, shows upregulation of the Eyes Shut Homolog (EYS) transcript, is predicted to be driven by OTX2, SOX4, and SOX11, and is enriched for axonogenesis and neurodifferentiation pathways. We analyzed 27,735 single-cell transcriptomes from eight MB tumours and recapitulated the observation that Group 4 MB cells best resemble UBC. We then found that two-thirds of Group 3 and Group 4 MB UBC-like cells best resemble human-enriched UBC 1 cells. Gene regulatory network analysis revealed that top regulators of Group 4 MB tumour cells include EOMES, SOX4, and SOX11. Our work provides initial evidence for human-enriched UBC states, and suggests that SOX4 and SOX11 may drive neurogenesis in UBC and gene expression in a subset of Group 4 MB tumour cells. Our findings shed light on genetic determinants of human cerebellar expansion and suggest that human models may be needed to recapitulate the oncogenesis of Group 3 and 4 MB.

genomics↗

bioRxiv2025

BRCA1 is a molecular correlate of cell proliferation in human brain development and in Group 3 and 4 medulloblastoma

The role of the BRCA1-mediated DNA damage repair pathway in regulating human brain development remains unknown, although it has been studied in mouse development. We report evidence for breast cancer type 1 susceptibility protein (BRCA1) being a molecular correlate of proliferation in human neural progenitor cells and in medulloblastoma (MB), a malignant pediatric hindbrain cancer whose cells resemble undifferentiated neural stem cells. In a computational search for molecules potentially keeping Group 3 (G3) and Group 4 (G4) MB tumour cells in a state of stalled differentiation, BRCA1 emerged as a leading candidate gene. We surveyed four independent transcriptomic datasets collectively spanning 142 human developing brain samples, multiple brain regions, and over 1.7 million single cells, and found that BRCA1 transcription is consistently enriched in human neural stem and progenitor cells, relative to differentiating or mature neurons. Across the human lifespan, BRCA1 expression is enriched in the brain during early development, particularly the first trimester of gestation. By analyzing 714 tumours, the largest transcriptomic survey of MB tumours to date, we found that BRCA1 expression is increased in carriers of isochromosome 17q (i17q) aberrations and in G4 MB tumours. Increased BRCA1 expression is associated with worse prognosis in G3 and G4 MB. In the developing cerebellum as well as in the cancer context, BRCA1 expression is correlated with transcription of the cell cycle and DNA damage repair pathways. When considered with previous mouse studies, our work is consistent with a model in which BRCA1 promotes genome surveillance in neural progenitors during human brain development and in G3 and G4 MB tumour growth, thus supporting proliferation.

genomics↗

bioRxiv2021

Plasticity in intrinsic excitability of hypothalamic magnocellular neurosecretory neurons in late-pregnant and lactating rats

Oxytocin and vasopressin secretion from the posterior pituitary gland are required for normal pregnancy and lactation. Oxytocin secretion is relatively low and constant under basal conditions but becomes pulsatile during birth and lactation to stimulate episodic contraction of the uterus for delivery of the fetus and milk ejection during suckling. Vasopressin secretion is maintained in pregnancy and lactation despite reduced osmolality (the principal stimulus for vasopressin secretion) to increase water retention to cope with the cardiovascular demands of pregnancy and lactation. Oxytocin and vasopressin secretion are determined by the action potential (spike) firing of magnocellular neurosecretory neurons of the hypothalamic supraoptic and paraventricular nucleus. In addition to synaptic input activity, spike firing depends on intrinsic excitability conferred by the suite of channels expressed by the neurons. Therefore, we analysed oxytocin and vasopressin neuron activity in anaesthetised non-pregnant, late-pregnant and lactating rats to test the hypothesis that intrinsic excitability of oxytocin and vasopressin neurons is increased in late pregnancy and lactation to promote oxytocin and vasopressin secretion required for successful pregnancy and lactation. Hazard analysis of spike firing revealed a higher incidence of post-spike hyperexcitability immediately following each spike in oxytocin neurons, but not in vasopressin neurons, in late pregnancy and lactation, which is expected to facilitate high frequency firing during bursts. Despite lower osmolality in late-pregnant and lactating rats, vasopressin neuron activity was not different between non-pregnant, late-pregnant and lactating rats, and blockade of osmosensitive {Delta}N-TRPV1 channels inhibited vasopressin neurons to a similar extent in non-pregnant, late-pregnant and lactating rats. Furthermore, supraoptic nucleus {Delta}N-TRPV1 mRNA expression was not different between non-pregnant and late-pregnant rats, suggesting that enhanced activity of {Delta}N-TRPV1 channels might maintain vasopressin neuron activity to increase water retention during pregnancy and lactation.

neuroscience↗

bioRxiv2020

Highly redundant neuropeptide volume cotransmission underlying episodic activation of the GnRH neuron dendron

The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic "KNDy" neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close but non-synaptic appositions with the GnRH neuron dendron. Confocal GCaMP6 calcium imaging demonstrated that, of the neurotransmitters co-expressed by KNDy neurons, only kisspeptin was able to activate the GnRH neuron dendron. The selective deletion of kisspeptin from KNDy neurons resulted in mice in which the synchronized behavior of the KNDy neurons was maintained but their ability to drive episodic hormone secretion was abolished. This indicates that KNDy neurons drive episodic hormone secretion through converse modes of highly redundant neuropeptide co-transmission orchestrated by differential postsynaptic neuropeptide receptor expression at their two target sites.

neuroscience↗

bioRxiv2020

The Degradation-promoting Roles of Deubiquitinases Ubp6 and Ubp3 in Cytosolic and ER Protein Quality Control

The quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remains unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.

cell biology↗