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- 저자 : Volovitch, M. (검색결과 2 건)
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Bernard, Clé,mence,Vincent, Clé,mentine,Testa, Damien,Bertini, Eva,Ribot, Jé,rô,me,Di Nardo, Ariel A.,Volovitch, Michel,Prochiantz, Alain Public Library of Science 2016 PLoS genetics Vol.12 No.5
<▼1><P>During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these “transfer” sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.</P></▼1><▼2><P><B>Author Summary</B></P><P>Classically, cell signaling is based on the secretion of molecules that bind cell surface receptors. Lipophilic agents can do without cell-surface receptors due to their ability to diffuse through the plasma membrane, but this is normally not the case for proteins, which cannot pass the membrane barrier. However, homeoprotein transcription factors represent an exception as they are secreted and internalized by live cells owing to two peptidic domains. An important illustration of this novel signaling mechanism is provided by Otx2, a homeoprotein that travels from the choroid plexus to specific inhibitory neurons in the cerebral cortex, where it regulates physiological plasticity throughout life. Because the two transfer peptides are in the DNA-binding domain of Otx2, it is impossible to mutate them without altering both cell signaling and cell-autonomous functions. We have therefore developed a mouse in which a secreted anti-Otx2 single-chain antibody can be induced to trap extracellular Otx2 while leaving its cell autonomous function untouched. We show that neutralizing extracellular Otx2 modifies the expression of plasticity genes in the visual cortex, thus providing the first genetic demonstration for homeoprotein signaling in a mammal.</P></▼2>
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