A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor

• Published in: PLoS genetics Vol. 12; no. 5; p. e1006035
• Main Authors: Bernard, Clémence, Vincent, Clémentine, Testa, Damien, Bertini, Eva, Ribot, Jérôme, Di Nardo, Ariel A, Volovitch, Michel, Prochiantz, Alain
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.05.2016; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies; Antibody Specificity - genetics; Antibody Specificity - immunology; Biochemistry, Molecular Biology; Biology and Life Sciences; Cerebral Cortex - immunology; Cerebral Cortex - metabolism; Deoxyribonucleic acid; Disease Models, Animal; DNA; Gene expression; Gene Expression Regulation; Genetic aspects; Health aspects; Humans; Immunoglobulins; Interneurons - immunology; Life Sciences; Mammals; Medicine and Health Sciences; Mice; Neuronal Plasticity - immunology; Neurons and Cognition; Neuroplasticity; Otx Transcription Factors - genetics; Otx Transcription Factors - immunology; Parvalbumins - biosynthesis; Physiology; Signal Transduction; Single-Chain Antibodies - genetics; Single-Chain Antibodies - immunology; Social Sciences; Statistical analysis; Transcription factors; Visual Cortex - immunology; Visual Cortex - metabolism
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006035

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.