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La mutación dirigida del gen que codifica el receptor NGF de baja afinidad p75 conduce a déficits en el sistema
1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Massachusetts 02142.
Cell
|May 29, 1992
Resumen
Los ratones que carecían del receptor de NGF de baja afinidad receptor de neurotrofinas p75 (p75NGFR) mostraron una reducción de las fibras nerviosas sensoriales, lo que condujo a la pérdida de sensibilidad al calor y úlceras. La restauración de p75NGFR rescató estos déficits sensoriales.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Genética La genética.
- Biología del desarrollo Biología del desarrollo.
Sus antecedentes:
- El receptor de neurotrofinas de baja afinidad, el receptor de neurotrofinas p75 (p75NGFR), está implicado en el desarrollo y la función neuronal.
- Su papel preciso en el desarrollo y mantenimiento de las neuronas sensoriales sigue siendo incompletamente entendido.
Objetivo del estudio:
- Investigar la función de p75NGFR en el desarrollo y la función de las neuronas sensoriales utilizando un modelo de ratón.
- Para determinar el impacto de la deficiencia de p75NGFR en la inervación sensorial, la sensibilidad térmica y la integridad de la piel.
Principales métodos:
- Generación de ratones con una mutación dirigida en el gen que codifica p75NGFR.
- Análisis inmunohistoquímico de la inervación sensorial y simpática en ratones mutantes y de tipo salvaje.
- Evaluación de la sensibilidad térmica y observación de la integridad de la piel en las extremidades distales.
- Complementación de la mutación mediante la introducción de un transgén p75NGFR humano.
Principales resultados:
- Los ratones homocigotos para la mutación p75NGFR exhibieron una inervación sensorial significativamente reducida en la piel de la almohadilla del pie, caracterizada por una disminución de las fibras peptídicas y inmunoreactivas de la sustancia P relacionadas con el gen de la calcitonina.
- Esta inervación defectuosa se correlacionó con una pérdida de sensibilidad al calor y el desarrollo de úlceras cutáneas graves en las extremidades distales, complicadas por infecciones bacterianas.
- La introducción de un transgén p75NGFR humano rescató la sensibilidad al calor, evitó la formación de úlceras y restauró la densidad de inervación sensorial.
- No se observaron alteraciones significativas en el tamaño de los ganglios simpáticos o en la densidad de la inervación simpática en el iris o en la glándula salival.
Conclusiones:
- El receptor de neurotrofinas p75 (p75NGFR) juega un papel crítico en el desarrollo y mantenimiento de la inervación de la neurona sensorial.
- La deficiencia de p75NGFR conduce a déficits sensoriales, incluida la disminución de la sensación de calor y la susceptibilidad a la ulceración de la piel.
- Dirigirse al p75NGFR puede ofrecer un potencial terapéutico para afecciones que involucran neuropatía sensorial.
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