Crosstalk among Wnt, SHH and Notch and the efect of Gal3 protein on the regulation of the proliferation of derived-neural stem cells reactive astrocytes

Abstract

Astrocyte activation is the main line of response to lesions in the central nervous system (CNS). The reactive astrocytes perform different roles, as the maintenance of the inflammatory response and secretion of factors that modify the extracellular matrix at the injury site. Recent studies show that reactive astrocytes undergo a process of dedifferentiation into neural stem cells (NSC). Gal3 is a protein that binds to galactosides, is widely expressed in neurogenic niches of the CNS and in NSC, acting as regulator of diverse intracellular signaling pathways as well as in molecular interactions in the extracellular microenvironment. In reactive astrocytes, the expression of Gal3 is predictive of dedifferentiation into NSC. In NSC intracellular environment, Gal3 can enter the nucleus where it regulates cellular proliferation. This activity has been related to the regulation of expression of cyclins and its inhibitors, mainly, cyclin A, cyclin D, p21WAF1/CIP1 and p27KIP1. Furthermore, it is known that Wnt, SHH and Notch signaling pathways are important for the function of NSC and progenitors in the neurogenic niches, considering that the crosstalk among this pathways have been demonstrated to be relevant for stem cell maintenance. Considering these findings, in this project we aim to study the effect of the crosstalk among Wnt, SHH and Notch signaling pathways in the generation of of reactive astrocytes-derived NSC from Gal3 knockout mice (Gal3-/-), and to evaluate the effect of Gal3 in those signaling pathways, with special interest in the control of proliferation. We hypothesize that Gal3 acts in the control of proliferation of reactive astrocytes-derived NSC throughout the action of Wnt, SHH and Notch. Understanding the mechanisms involved in the cellular and molecular response of the organism to injuries and degeneration of the CNS could serve as a basis to the development of new drugs and therapeutic strategies to treat pathologies that affect the brain.