RESUMO
The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions in vivo. We have examined the role of ERK2 in neural development by conditional inactivation of the murine mapk1/ERK2 gene in neural progenitor cells of the developing cortex. ERK MAP kinase (MAPK) activity in neural progenitor cells is required for neuronal cell fate determination. Loss of ERK2 resulted in a reduction in cortical thickness attributable to impaired proliferation of neural progenitors during the neurogenic period and the generation of fewer neurons. Mutant neural progenitor cells remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The mutant mice displayed profound deficits in associative learning. Importantly, we have identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children, who have reduced ERK2 levels, exhibit microcephaly, impaired cognition, and developmental delay. These findings demonstrate an important role for ERK2 in cellular proliferation and differentiation during neural development as well as in cognition and memory formation.
Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/enzimologia , Cognição/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Neurônios/enzimologia , Células-Tronco/enzimologia , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células , Células Cultivadas , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação Enzimológica da Expressão Gênica/genética , Deficiências da Aprendizagem/enzimologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Neurônios/citologia , Células-Tronco/citologiaRESUMO
There are striking differences in the behavioral response to social defeat between male and female Syrian hamsters. Whereas males exhibit a prolonged behavioral response to defeat (i.e., conditioned defeat), many females remain aggressive or show only a transient submissive response following defeat. The current study tested the hypothesis that sex steroids underlie this differential behavioral responsivity to social defeat. Female hamsters were ovariectomized and implanted with Silastic capsules containing estradiol (E(2)), testosterone (T), progesterone (P), dihydrotestosterone (DHT), or a blank capsule (no hormone replacement). After a 3-week recovery period, each subject was placed inside the home cage of a larger, more aggressive female for four 5-min defeat trials. The following day, each animal was tested for conditioned defeat by testing it in its own home cage in the presence of a smaller, non-aggressive intruder. Submissive, aggressive, social, and nonsocial behaviors were subsequently scored. Hamsters receiving E(2) or T displayed significantly lower levels of submissive behavior than did animals receiving P, DHT, or no hormone replacement. There were no significant differences in aggressive behavior among groups. These data suggest that gonadal hormones can influence submissive behavior in female hamsters. Collectively, these results suggest that the sex differences observed in conditioned defeat may, in part, be explained by sex differences in circulating gonadal hormones.