Omics profiling of cortical progenitor cells in evolution and cancer

• Autores: Rafael Soler Ortuño
• Directores de la Tesis: Víctor Borrell Franco (dir. tes.), José Pascual López Atalaya Martínez (tut. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2025
• Idioma: español
• Tribunal Calificador de la Tesis: Ángel Barco Guerrero (presid.), Darío Jesús García Lupiáñez (secret.), Christian Mayer (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
• Materias:
  • Matemáticas
    • Ciencia de los ordenadores
      • Informática
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• Resumen

  • The evolution of cortical neurogenesis has been fundamental to the development of the complex mammalian brain. Disruptions in these processes underlie various neurodevelopmental disorders and cancers, such as embryonal tumors with multilayered rosettes (ETMRs). This thesis integrates comparative transcriptomics, epigenomics, and single-cell RNA sequencing (scRNA-seq) to investigate the molecular and cellular mechanisms governing cortical neurogenesis and its pathological dysregulation in ETMRs.

    The first part of this work explores the evolutionary mechanisms of cortical neurogenesis in amniotes by comparing transcriptomic and epigenomic profiles of apical radial glial cells (aRGCs) between mice, chicks, and snakes. We researched key regulators, such as Sall1, miR-3607, Cux2, Robo1/2 or Dll1, that govern neurogenic modes and cortical folding, shedding light on the conserved and divergent pathways that shaped cortical evolution.

    In the second part, the existence of membrane-bound transcription factors (MTFs) in mammals is investigated. Hundreds of potential MTFs were identified, many localizing to the nucleus and suggesting roles in regulating gene expression during neurogenesis and cancer. Among these, Robo1 was identified as a candidate MTF, predicted to possess transcriptional regulatory potential. These findings reveal a previously underexplored regulatory layer and its potential implications for cortical development and tumor biology.

    The third part evaluates the Rx-Cre-DicerF/F (Rx-Dicer1) mutant mouse as a preclinical model for ETMR and demonstrates that it is superior to the previously established GBS model. Transcriptomic profiling at embryonic stages E11.5 and E17.5 shows that Rx-Dicer1 mutants not only recapitulate key histological and molecular features of ETMRs but also share a greater proportion of ETMR signature genes, such as LIN28A/B, PRTG, and IGF2BPs. Dysregulation of pathways like PI3K/AKT/mTOR further highlights its relevance. scRNA-seq identifies tumor-specific populations of neuroepithelial-like cells and their loss of aRGC identity. RNA velocity and transcriptional trajectory analyses reveal a disrupted differentiation process, with neuroepithelial-like cells becoming overproliferative and contributing to rosette formation.

    Together, this research uncovers the evolutionary and pathological mechanisms driving cortical neurogenesis and its dysregulation in ETMRs. The findings establish the Rx-Dicer1 mutant mouse as a more faithful model for ETMR than GBS and provide insights into potential therapeutic targets, such as LIN28A/B, PRTG and PI3K/AKT/mTOR signaling, for treating aggressive brain tumors. By bridging evolutionary biology and cancer research, this thesis advances our understanding of neurogenesis and its role in health and disease.