Novel functions of minibrain in the regulation of cell cycle, neuronal differentiation and asymmetric division in drosophila

• Autores: Shaikh Mirja Nurunnabi
• Directores de la Tesis: Francisco Tejedor Rescalvo (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: Sonsoles Campuzano Corrales (presid.), Javier Morante Oria (secret.), Nuria Paricio (voc.), José María Frade López (voc.), Antonio Baonza Cuenca (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
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• Resumen

  • Generating the appropriate number of distinct classes of neurons at the right time and place is essential for constructing functional neuronal circuits during brain development. This task is achieved through the tight coordination of proliferation, specification, and terminal differentiation of neuronal progenitor cells. However, how these crucial steps are coordinated during brain development and their underlying molecular mechanisms remain largely unknown.

    The minibrain (mnb) gene, the Drosophila melanogaster ortholog of the Down syndrome candidate gene DYRK1A, encodes a serine-threonine protein kinase which is involved in several brain development processes, particularly in neural proliferation and neurogenesis. In this Thesis, we have investigated novel functions of Mnb in neurogenesis and their underlying mechanisms using the larval brain of Drosophila melanogaster as an experimental model system.

    We present evidences that Mnb promotes the cell cycle exit of new born neuronal precursors, known as ganglion cells (GCs), through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27Kip1. On one hand, Mnb upregulates the expression of the pan-neural transcription factor (TF) Asense, which promotes Dacapo expression. On the other hand, Mnb induces the expression of Prospero, a homeodomain TF that in turn inhibits the expression of Deadpan, another pan-neural TF that represses dacapo. We have also found that Mnb promotes the expression of the neuronal specific RNA regulator Elav in early differentiating neuronal precursors suggesting a role of Mnb in neuronal differentiation. Interestingly, evidences are here shown that independently of its action on Asense, Mnb controls the expression of CyclinA, Cyclin B and String (Cdc25), three key regulators of the G2-M transition of the cell cycle. This strongly suggests a novel mechanism for the regulation of the cell cycle of neural progenitors by Mnb. In addition, we found that Mnb is involved in the regulation of polarity and asymmetry of neural progenitor cell division during Drosophila optic lobe development. Finally, we found that Asense promotes the neuroepithelia (NE) to neuroblast (NB) transition which is a key step in Drosophila postembryonic neurogenesis. Together, our results suggest that Mnb fulfills multiple functions in neurogenesis by regulating the cell cycle and asymmetric cell division of neural progenitors, and the cell cycle exit and terminal differentiation of neuronal precursors, possibly controlling in this manner the balance between proliferation and differentiation during brain development, which is known to be deregulated in Down syndrome and microcephalies.