RESUMO
Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD.
Assuntos
Adaptação Fisiológica/genética , Proteína 3 de Resposta de Crescimento Precoce/genética , Comportamento Exploratório/fisiologia , Hipocampo/metabolismo , Plasticidade Neuronal/genética , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Corticosterona/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Genes Precoces/genética , Habituação Psicofisiológica/genética , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Potenciação de Longa Duração/genética , Depressão Sináptica de Longo Prazo/genética , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
The cephalic gap genes specify anterior head development in the Drosophila embryo. However, the mechanisms of action of these genes remain poorly understood. Here, we focused on the cephalic gap gene orthodenticle (otd), which establishes a specific region of the anterior head. It has been proposed that otd acts in a combinatorial fashion with the cephalic gap genes empty spiracles (ems) and buttonhead (btd) to assign segmental identities in this region. To test this model, we used a heat-inducible transgene to generate pulses of ubiquitous otd expression during embryonic development. Ectopic otd expression caused significant defects in head formation, including the duplication of sensory structures derived from otd-dependent segments. However, these defects do not appear to result from the transformation of head segment identities predicted by the combinatorial model. Instead, they correlate with specific regulatory effects of otd on the expression of the segment polarity genes engrailed (en) and wingless (wg). Ectopic otd expression also caused the loss of head structures derived from the maxillary segment, which lies posterior to the otd domain. We show that this effect is associated with otd repression of the homeotic selector gene Deformed (Dfd).
Assuntos
Padronização Corporal/genética , Proteínas de Drosophila , Regulação da Expressão Gênica no Desenvolvimento , Genes de Insetos , Cabeça/embriologia , Proteínas de Homeodomínio/biossíntese , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/biossíntese , Drosophila/embriologia , Drosophila/genética , Olho/embriologia , Proteínas de Homeodomínio/genética , Proteínas Proto-Oncogênicas/biossíntese , Órgãos dos Sentidos/embriologia , Distribuição Tecidual , Fatores de Transcrição/biossíntese , Proteína Wnt1RESUMO
In the trunk of the Drosophila embryo, the segment polarity genes are initially activated by the pair-rule genes, and later maintain each other's expression through a complex network of cross-regulatory interactions. These interactions, which are critical to cell fate specification, are similar in each of the trunk segments. To determine whether segment polarity gene expression is established differently outside the trunk, we studied the regulation of the genes hedgehog (hh), wingless (wg), and engrailed (en) in each of the segments of the developing head. We show that the cross-regulatory relationships among these genes, as well as their initial mode of activation, in the anterior head are significantly different from those in the trunk. In addition, each head segment exhibits a unique network of segment polarity gene interactions. We propose that these segment-specific interactions evolved to specify the high degree of structural diversity required for head morphogenesis.
