Robo receptors regulate neurogenesis along vertebrate brain evolution

• Autores: Adrian Cardenas Castello
• Directores de la Tesis: Víctor Borrell Franco (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2016
• Idioma: inglés
• Tribunal Calificador de la Tesis: María Isabel Fariñas Gómez (presid.), Eduardo de Puelles Martínez de la Torre (secret.), Eloísa Herrera González (voc.), François Guillemot (voc.), Ricardo Pardal Redondo (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Neurociencias
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• Resumen

  • The brain is the most complex organ ever developed, in which the sensory information is received, processed, integrated and stored before giving rise to a motor and/or behavioral response. As a part of the brain, the cerebral cortex or neocortex is considered the pinnacle of evolution. This structure reaches its maximum potential in mammals, particularly in the human brain, where it underlies the most intricate human behaviors such as language, emotions, attention, abstract thinking… The correct development of the cerebral cortex requires an exquisite regulation of every necessary step for the formation of its neurons: proliferation, neuronal differentiation and migration. Perturbation of any one of these steps commonly results in significant anomalies. Our main interest focuses on studying the mechanisms that control the perfect balance between proliferation and neurogenesis in the cerebral cortex. We know that in the mouse neocortex there are two main types of neuronal progenitors: apical Radial Glia Cells (aRGCs) and Intermediate Progenitor Cells (IPCs). We have confirmed that the majority of neurons in the cortex are produced through indirect neurogenesis via IPCs.

    We have determined that Robo receptors are important regulators for the formation of IPCs, which until then they had been almost only studied in differentiated cells. The absence of Robo receptor signaling causes an overproduction of IPCs through interactions with the Notch signaling pathway, modulating the dynamics of progenitor cells. Using a comparative study between the development of the cortex and more ancient structures we have found a higher predominance of direct neurogenesis in the latter, that is formation of neurons directly from aRGCs. This has essential implications in regulating the size of these structures because, in a given period of time, direct neurogenesis will produce only half as many neurons compared with indirect neurogenesis. Likewise, in the brain structures of birds and reptiles equivalent to the mammalian cerebral cortex have demonstrated that direct neurogenesis is the predominant or exclusive mode. Thus we have found a correlation between the antiquity of the structure and the mode or proportion of each type of neurogenesis. In more evolved structures (i.e. neocortex) there is a shift from direct to indirect neurogenesis that allows a higher expansion and complexity.

    In this context, we have also described that Robo receptors are essential to modulate the mode of neurogenesis and, like we found previously, they do so also through the cooperation with the Notch pathway. Whereas in progenitor cells of the reptile cortex Robo signaling is very high, the experimental attenuation of Robo signaling (as it occurs in the mammalian cortex) allows the formation of basal progenitors similar to intermediate progenitors in mouse, and a shift towards indirect neurogenesis. We have demonstrated this in several animals and brain structures with different phylogenic antiquity, allowing us to conclude that Robo receptors are a key elements in the transition towards indirect neurogenesis during evolution and, consequently, they are essential for cerebral cortex expansion.