Biology subjects

Turan, S.

Publications and source records attributed to Turan, S..

3 recordsLinked to original sources

bioRxiv2025

The neuronal fate determinants SOX4/11 control mitotic fidelity of adult hippocampal precursor cells

In adult hippocampal neurogenesis, fast dividing intermediate progenitor cells (IPCs) ensure the production of a larger number of neurons from a limited pool of slow dividing radial-glia-like neural stem cells. Here, we demonstrate that the neuronal fate determining and lineage-specific transcription factors SOX4 and SOX11 are essential to faithfully execute mitosis in IPCs. In vivo, combined deletion of SOX4 and SOX11 results in death of IPCs and abolishes the generation of new neurons. In vitro analyses of SOX4/11-deficient precursors revealed mitosis defects including chromosome segregation errors, centrosomal errors and cytokinesis defects. SOX4/11-deficient precursors frequently featured micronuclei and DNA bridges and showed a pro-inflammatory signaling profile, suggesting the induction of death by mitotic catastrophe. Importantly, analysis of the developing mouse spinal cord and of human pluripotent stem cell-derived brain organoids indicate that SOXC transcription factors are essential for mitotic fidelity of neural precursor cells across ontogeny and species. The data raise the interesting possibility that mitotic programs in precursor cells are controlled in a lineage-specific manner.

cell biology↗

bioRxiv2025

Aberrant formation of long-range projections across different neurodevelopmental disorders converges on molecular and cellular nexuses

Establishing long-range connections during human brain development is an intricate multi-step process disturbed in many neurodevelopmental disorders (NDDs). The aberrant formation of these connections is caused by mutations in a plethora of different genes with distinct molecular functions, triggering the question of whether there are common key downstream mediators at which different pathologies are converging. We employed brain organoids to model early human brain developmental aspects of Coffin-Siris-like 9, Opitz BBB/G, and Pitt-Hopkins syndromes. These NDDs are caused by mutations in SOX11, MID1, and TCF4 respectively, and are characterized by a multitude of distinct symptoms yet share alterations in long-range projections as a common feature. Here, we uncover that mutations in all three genes phenotypically converge, showing impaired neurite extension with increased tortuosity and decreased growth speed resulting in shorter beelines. Moreover, the mutant neurites exhibit a decrease in growth persistence providing a conceptual framework explaining why long- but not short-range connections are affected. Correlating with the converging cellular phenotype, molecular characterization revealed a striking convergence on signaling pathways implicated in the interaction of neurites with their extracellular environment. In-silico modeling and perturbation of neurite outgrowth suggest that altered neurite-extracellular environment interactions are sufficient to recapitulate the mutant phenotypes but also facilitate the prediction of specific parameters causing disturbed neurite growth in mutant neurons.

developmental biology↗

bioRxiv2023

Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium

Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.

immunology↗