Biology subjects

Haldipur, P.

Publications and source records attributed to Haldipur, P..

5 recordsLinked to original sources

bioRxiv2026

Ependymomas are cancers of the pre-neural crest/roof plate lineage

Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest/roof plate (Pre-NC/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.

developmental biology↗

bioRxiv2026

Extracellular matrix defects destabilise apical cytoarchitecture and mechanical properties during early Down syndrome neurodevelopment

Down syndrome (DS) is associated with altered brain development, especially in the cerebellum. However, how trisomy 21 (TS21) is linked to cerebellar defects remains poorly understood. Cerebellar organoids reveal that TS21 leads to extracellular matrix (ECM) alterations, perturbing downstream pathways linked to reduction of apical RAB11+ endosomes. These changes lead to impaired apical maintenance and altered progenitor composition. Significantly, ECM-enriched culture rescues apical defects in TS21 organoids, supporting a functional role for ECM in preserving apical organisation and progenitor niche integrity. In the developing human DS cerebellum and 2D neural cultures, where exogenous ECM is present, severe epithelial disorganisation is attenuated. Nevertheless, ECM organisation and mechanical properties remain altered in 2D cultures. Our findings identify TS21-driven ECM abnormalities as a mechanism impairing apical integrity, progenitor composition and mechanical proprieties in neural stem cell models of DS. Altogether, we established apical maintenance instability as an early developmental defect contributing for DS neuropathology.

Developmental Biology↗

bioRxiv2025

Elucidating Neurodevelopmental Trajectories in Cancer with Topic Modeling: Revealing Persistent External Granule Layer Lineages in Medulloblastoma

Single-cell transcriptomics transformed our understanding of cellular heterogeneity, yet cross-dataset comparison remains fundamentally limited by batch effects, technology differences, and inconsistent annotation frameworks. These challenges have impeded efforts to connect developmental programs with disease states which creates a critical gap for understanding pediatric cancers with suspected developmental origins. Here, we demonstrate that topic modeling, an unsupervised natural language processing technique, overcomes these barriers by learning transferable transcriptional genetic signatures that generalize across datasets, technologies, and biological contexts without requiring data integration. Applying this framework to over one million fetal cerebellar nuclei, we identify seven distinct topics that capture the developmental spectrum of rhombic lip progenitors through external granule layer (EGL) differentiation, including transitional states missed by conventional clustering. These topics transfer successfully across sequencing technologies (SPLiT-seq to sci-RNA-seq3), developmental timepoints, species (human to mouse), and from single-cell to bulk RNA sequencing of 876 medulloblastoma tumors. We reveal that Sonic hedgehog (SHH) medulloblastoma subtypes retain these topics, corresponding to distinct stages of EGL development. Our findings highlight that developmental timing at tumor initiation fundamentally shapes tumor biology, with immediate implications for subtype-specific therapeutic strategies in pediatric brain cancer. Our workflow establishes topic modeling as a scalable solution for mining expanding genomic atlases with broad applications across different datasets, technologies, and biological contexts.

bioinformatics↗

bioRxiv2020

BMP signalling facilitates transit amplification in the developing cerebellum.

The external granule layer (EGL) is a transient proliferative layer that gives rise to cerebellar granule cell neurons. Extensive EGL proliferation characterises the foliated structure of amniote cerebella, but the factors that regulate EGL formation, amplification within it, and differentiation from it, are incompletely understood. Here, we characterise bone morphogenic protein (BMP) signalling during cerebellar development in chick and human and show that while in chick BMP signalling correlates with external granule layer formation, in humans BMP signalling is maintained throughout the external granule layer after the onset of foliation. We also show via Immunohistochemical labelling of phosphorylated Smad1/5/9 the comparative spatiotemporal activity of BMP signalling in chick and human. Using in-ovo electroporation in chick, we demonstrate that BMP signalling is necessary for subpial migration of granule cell precursors and hence the formation of the external granule layer (EGL) prior to transit amplification. However, altering BMP signalling does not block the formation of mature granule neurons but significantly disrupts that pattern of morphological transitions that accompany transit amplification. Our results elucidate two key, temporally distinct roles for BMP signalling in vivo in organising first the assembly of the EGL from the rhombic lip and subsequently the tempo of granule neuron production within the EGL. Significance statementImproper development of cerebellar granule neurons can manifest in a plethora of neurodevelopmental disorders, including but not limited to medulloblastoma and autism. Many studies have sought to understand the role of developmental signalling pathways in granule cell neurogenesis, using genetic manipulation in transgenic mice. To complement these insights, we have used comparative assessment of BMP signalling during development in chick and human embryos and in vivo manipulation of the chick to understand and segregate the spatiotemporal roles of BMP signalling, yielding important insights on evolution and in consideration of future therapeutic avenues that target BMP signalling.

developmental biology↗

bioRxiv2020

Spatial and single-cell transcriptional landscape of human cerebellar development

ABSTRACTCerebellar development and function require precise regulation of molecular and cellular programs to coordinate motor functions and integrate network signals required for cognition and emotional regulation. However, molecular understanding of human cerebellar development is limited. Here, we combined spatially resolved and single-cell transcriptomics to systematically map the molecular, cellular, and spatial composition of early and mid-gestational human cerebellum. This enabled us to transcriptionally profile major cell types and examine the dynamics of gene expression within cell types and lineages across development. The resulting ‘Developmental Cell Atlas of the Human Cerebellum’ demonstrates that the molecular organization of the cerebellar anlage reflects cytoarchitecturally distinct regions and developmentally transient cell types that are insufficiently captured in bulk transcriptional profiles. By mapping disease genes onto cell types, we implicate the dysregulation of specific cerebellar cell types, especially Purkinje cells, in pediatric and adult neurological disorders. These data provide a critical resource for understanding human cerebellar development with implications for the cellular basis of cerebellar diseases.Competing Interest StatementA.B.R, C.R., and G.Se. are shareholders of Split Bioscience.View Full Text

developmental biology↗