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J Neurosci ; 19(22): 9913-27, 1999 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-10559400

RESUMEN

Activation of erbB-1 receptors by glial TGFalpha has been shown to be a component of the developmental program by which the neuroendocrine brain controls mammalian sexual development. The participation of other members of the erbB family may be required, however, for full signaling capacity. Here, we show that activation of astrocytic erbB-2/erbB-4 receptors plays a significant role in the process by which the hypothalamus controls the advent of mammalian sexual maturation. Hypothalamic astrocytes express both the erbB-2 and erbB-4 genes, but no erbB-3, and respond to neuregulins (NRGs) by releasing prostaglandin E(2) (PGE(2)), which acts on neurosecretory neurons to stimulate secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development. The actions of TGFalpha and NRGs in glia are synergistic and involve recruitment of erbB-2 as a coreceptor, via erbB-1 and erbB-4, respectively. Hypothalamic expression of both erbB-2 and erbB-4 increases first in a gonad-independent manner before the onset of puberty, and then, at the time of puberty, in a sex steroid-dependent manner. Disruption of erbB-2 synthesis in hypothalamic astrocytes by treatment with an antisense oligodeoxynucleotide inhibited the astrocytic response to NRGs and, to a lesser extent, that to TGFalpha and blocked the erbB-dependent, glia-mediated, stimulation of LHRH release. Intracerebral administration of the oligodeoxynucleotide to developing animals delayed the initiation of puberty. Thus, activation of the erbB-2-erbB-4 receptor complex appears to be a critical component of the signaling process by which astrocytes facilitate the acquisition of female reproductive capacity in mammals.


Asunto(s)
Astrocitos/fisiología , Corteza Cerebral/fisiología , Receptores ErbB/fisiología , Hipotálamo/fisiología , Neurregulinas/fisiología , Receptor ErbB-2/fisiología , Maduración Sexual/fisiología , Animales , Neoplasias de la Mama , Corteza Cerebral/crecimiento & desarrollo , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/fisiología , Dinoprostona/sangre , Receptores ErbB/genética , Estradiol/farmacología , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes erbB-1 , Humanos , Hipotálamo/crecimiento & desarrollo , Neurregulinas/genética , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Oligodesoxirribonucleótidos Antisentido/farmacología , Proteínas Oncogénicas v-erbB , Ovariectomía , Fosforilación , Fosfotirosina/metabolismo , Embarazo , Progesterona/farmacología , Ratas , Ratas Sprague-Dawley , Receptor ErbB-2/genética , Receptor ErbB-4 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Transfección , Células Tumorales Cultivadas
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