Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
Lrig transmembrane proteins: Key regulators of neurotrophic activity and neuronal connectivity.\nNeurotrophic factors are a group of secreted and diffusible molecules that play a key role during the development of the central and peripheral nervous system, promoting neuronal survival, proliferation,...
Guardado en:
| Autor principal: | |
|---|---|
| Otros Autores: | |
| Formato: | Tesis doctoral acceptedVersion |
| Publicado: |
Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
2020
|
| Materias: | |
| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6408 https://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6408.dir/6408.PDF |
| Aporte de: |
| Sumario: | Lrig transmembrane proteins: Key regulators of neurotrophic activity and neuronal connectivity.\nNeurotrophic factors are a group of secreted and diffusible molecules that play a key role during the development of the central and peripheral nervous system, promoting neuronal survival, proliferation, axonal and dendritic growth and establishing appropriate patterns of neuronal connectivity. The signals induced by these factors involve the phosphorylation of tyrosine kinase type receptors (RTKs) which, in turn, activate key intracellular signaling pathways for the control of cellular physiology and the regulation of neuronal development.\nThe activity of RTKs and the correct regulation of them are considered of utmost importance to establish appropriate activation thresholds, given that exacerbated or diminished activities can generate failures in the appropriate development of an organism and as a consequence, the appearance of proliferative or neurodegenerative pathologies.\nRecent studies have demonstrated the importance of intrinsic factors as a key mechanism to control the signals triggered by neurotrophic factors in certain neuronal subpopulations.\nIn particular, the Lrig transmembrane proteins (Leucine-rich repeat and immunoglobulin-like domain proteins), constitute a family of three proteins, (Lrig1, Lrig2 and Lrig3) which are enriched in the nervous system and have been functionally characterized as endogenous regulators of the activity of growth factors and neurotrophic factors.\nThe aim of this thesis was to identify and characterize new functions of the Lrig family of proteins along the development of the dorsal root ganglia and peripheral sensory innervation, as well as during cortical neurogenesis.\nIn the first section of this thesis (Chapter I), the Lrig family of proteins were characterized as negative modulators of the biological effects induced by the GDNF family ligands and their receptor, Ret, in sensory neurons derived from the dorsal root ganglia (DRG). The assays shown here demonstrate that Lrig1 and Lrig3 cooperate to regulate the axonal growth of sensory neurons induced by GDNF and NRTN neurotrophic factors, non-peptidergic skin sensory innervation and sensitivity to cold stimuli. Together, these findings show that Lrig proteins, specifically Lrig1 and Lrig3, fulfill essential functions during the development of the peripheral nervous system, particularly regulating the development of non peptidergic nociceptive neurons.\nOn the other hand, the role of Lrig1 protein during the development of neural cortical progenitors was assessed (Chapter II). Lrig1 was identified as a negative regulator of the proliferation of cortical neurogenic progenitors, functioning as an inhibitor of the mitogenic activity of FGF2. It was shown that Lrig1 maintains cortical neural precursors in a state of quiescence and that its deletion promotes proliferation and self-renewal. Taken together, these results indicate that Lrig1 plays a key physiological role during proliferative events, functioning as a homeostatic regulator of glutamatergic cortical neurogenesis.\nIn conclusion, in this manuscript, new functions of Lrig family of proteins have been identified, acting, both temporally and spatially, as modulators of signaling and biological effects of neurotrophic factors relevant for the development of central and peripheral nervous system. |
|---|