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,...

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Autor principal:	De Vincenti, Ana Paula
Otros Autores:	Ledda, Fernanda
Formato:	Tesis doctoral acceptedVersion
Publicado:	Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica 2020
Materias:	Factores neurotróficos RTK Ret FGFR1 Familia Lrig Ganglios de la raíz dorsal Progenitores neurales corticales Lrig family Neurotrophic factors Dorsal root ganglia (DRG) Cortical progenitors Ciencias de la vida
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:	Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires

id	I28-R145-HWA_6408
record_format	dspace
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-145
collection	Repositorio Digital de la Universidad de Buenos Aires (UBA)
topic	Factores neurotróficos RTK Ret FGFR1 Familia Lrig Ganglios de la raíz dorsal Progenitores neurales corticales Lrig family Neurotrophic factors RTK Ret FGFR1 Dorsal root ganglia (DRG) Cortical progenitors Ciencias de la vida
spellingShingle	Factores neurotróficos RTK Ret FGFR1 Familia Lrig Ganglios de la raíz dorsal Progenitores neurales corticales Lrig family Neurotrophic factors RTK Ret FGFR1 Dorsal root ganglia (DRG) Cortical progenitors Ciencias de la vida De Vincenti, Ana Paula Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
topic_facet	Factores neurotróficos RTK Ret FGFR1 Familia Lrig Ganglios de la raíz dorsal Progenitores neurales corticales Lrig family Neurotrophic factors RTK Ret FGFR1 Dorsal root ganglia (DRG) Cortical progenitors Ciencias de la vida
description	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.
author2	Ledda, Fernanda
author_facet	Ledda, Fernanda De Vincenti, Ana Paula
format	Tesis doctoral Tesis doctoral acceptedVersion
author	De Vincenti, Ana Paula
author_sort	De Vincenti, Ana Paula
title	Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
title_short	Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
title_full	Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
title_fullStr	Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
title_full_unstemmed	Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
title_sort	las proteínas transmembrana lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal
publisher	Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
publishDate	2020
url	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
work_keys_str_mv	AT devincentianapaula lasproteinastransmembranalrigreguladoresclavesdelaactividadneurotroficaydelaconectividadneuronal
_version_	1840330168966578176
spelling	I28-R145-HWA_64082025-06-24 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. Fil: De Vincenti, Ana Paula. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Ledda, Fernanda Adamo, Ana Paratche, Gustavo De Vincenti, Ana Paula 2020-03-10 Las proteínas transmembrana Lrig: Reguladores claves de la actividad neurotrófica y de la conectividad neuronal.\nLos factores neurotróficos son un grupo de moléculas secretadas y difusibles que cumplen un rol clave durante el desarrollo del sistema nervioso central y periférico, promoviendo la sobrevida neuronal, la proliferación, el crecimiento axonal y dendrítico y el establecimiento de patrones adecuados de conectividad neuronal. Las señales inducidas por estos factores involucran la fosforilación de receptores del tipo tirosina kinasa (RTKs) que, a su vez, activan vías de señalización intracelular claves para el control de la fisiología celular y la regulación del desarrollo neuronal.\nLa actividad de los RTKs y la correcta regulación de los mismos son consideradas de suma importancia para establecer umbrales de activación adecuados, ya que actividades exacerbadas o disminuidas de los mismos podrían generar fallas en el correcto desarrollo de un organismo y como consecuencia, la aparición de patologías proliferativas o neurodegenerativas.\nEstudios recientes han demostrado la importancia de los factores intrínsecos como un mecanismo clave para controlar las señales disparadas por los factores neurotróficos en determinadas subpoblaciones neuronales.\nEn particular, las proteínas transmembrana Lrig (Leucine?rich repeat and immunoglobulin-like domain proteins), constituyen una familia de tres proteínas, Lrig1, Lrig2 y Lrig3, las cuales se encuentran enriquecidas en el sistema nervioso y han sido caracterizadas funcionalmente como reguladores endógenos de la actividad de receptores de factores de crecimiento y neurotróficos.\nEl objetivo de la presente tesis consistió en identificar y caracterizar nuevas funciones de la familia de proteínas Lrig durante el desarrollo de los ganglios de la raíz dorsal y de la inervación sensorial periférica, así como también durante el desarrollo de los progenitores neurales corticales.\nEn la primera sección de la tesis (capítulo I), se caracterizó a la familia de proteínas Lrig como moduladores negativos de los efectos biológicos inducidos por los ligandos de la familia de GDNF y su receptor tirosina quinasa Ret en neuronas sensoriales derivadas del ganglio de la raíz dorsal (GRD). Los estudios realizados permitieron demostrar que Lrig1 y Lrig3 cooperan para regular el crecimiento axonal de neuronas sensoriales inducido por los factores neurotróficos GDNF y NRTN, la inervación sensorial cutánea de tipo no peptidérgica y la sensibilidad a estímulos fríos. Estos hallazgos demuestran que las proteínas Lrig, específicamente Lrig1 y Lrig3, cumplen funciones esenciales durante el desarrollo del sistema nervioso periférico, particularmente regulando el desarrollo de las neuronas nociceptivas de tipo no peptidérgico.\nPor otro lado, se estudió el rol de la proteína Lrig1 durante el desarrollo de los progenitores corticales neurales (capítulo II). Se presentaron evidencias que identifican a Lrig1 como un regulador negativo de la proliferación de los progenitores neurogénicos corticales, funcionando como un inhibidor de la actividad mitogénica de FGF2. Se demostró que Lrig1 mantiene a los precursores neurales corticales en un estado de quiescencia y que la deleción del mismo promueve la proliferación y autorrenovación. En su conjunto, estos resultados indican que Lrig1 cumple un rol fisiológico clave durante los eventos proliferativos, funcionando como un regulador homeostático de la neurogénesis cortical glutamatérgica.\nDe esta manera, en este trabajo de tesis doctoral se han identificado nuevas funciones de la familia de proteínas Lrig, como moduladores tanto temporales como espaciales de la señalización y de los efectos biológicos inducidos por diversos factores neurotróficos relevantes para el desarrollo del sistema nervioso central y periférico. application/pdf Pasquini, Juana Saravia, Flavia Aquino, Jorge Factores neurotróficos RTK Ret FGFR1 Familia Lrig Ganglios de la raíz dorsal Progenitores neurales corticales Lrig family Neurotrophic factors RTK Ret FGFR1 Dorsal root ganglia (DRG) Cortical progenitors Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencias de la vida Doctora de la Universidad de Buenos Aires en Ciencias de la Salud Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion 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

Las proteínas transmembrana Lrig : reguladores claves de la actividad neurotrófica y de la conectividad neuronal

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