Genetic, structural and electrophysiological analyis of the zinc finger transcription factor Bcl11b/Ctip2 during formation and maintenance of hippocampal mossy fiber synapses
Developmental Biology
Final Report Abstract
The hippocampus has a distinct role in memory processing, learning, spatial navigation, and emotional behavior. The dentate gyrus with its unique properties, such as postnatal development, lifelong regeneration and peculiar synaptic connections with distinct structural and plasticity features, is an integral structure for hippocampal function. Thus, understanding the mechanisms regulating the development and function of the dentate gyrus is essential. The transcription factor Bcl11b/Ctip2 is expressed in the dentate gyrus during development and in adulthood, and we have previously shown that forebrain-specific ablation of Bcl11b/Ctip2 in the developing brain significantly impairs the dentate gyrus morphology, reduces the proliferation of the neuronal progenitor cells, leads to cell loss, and impairs the neuronal differentiation and spatial organization of mossy fibers. Here, we show that adultspecific ablation of Bcl11b in the dentate gyrus of mice impairs the survival, differentiation and functional integration of adult born granule cells. Loss of Bcl11b/Ctip2 in both the developing and the mature dentate gyrus negatively affected the learning and memory capacities of the animals. Furthermore, we were able to show that Bcl11b/Ctip2 has an important role in the development and maintenance of the mossy fiber circuitry. Deletion of Bcl11b/Ctip2 selectively in adult mice reduced the number of mossy fiber synapses, impaired the ultrastructural complexity of the mossy fiber boutons and the recruitment of the synaptic vesicles and led to a dramatic decline in the long-term potentiation. Stereotaxic injection of AAV expressing the direct transcriptional target C1ql2 into Bcl11b/Ctip2 mutant dentate gyrus rescued the recruitment of synaptic vesicles and the expression of long-term potentiation, while knockdown of C1ql2 in wild-type dentate gyrus recapitulated the Bcl11b phenotype. Moreover, we demonstrated C1ql2 to exert its functions through direct interaction with a specific Neurexin 3 isoform, Neurexin3(25b+). Interruption of C1ql2-Neurexin3(25b+) interaction by expression of a binding-deficient C1ql2 mutant or by deletion of Neurexin 3 in the dentate gyrus recapitulated major parts of the Bcl11b as well as C1ql2 mutant phenotype. Taken together, we have extensively demonstrated the transcription factor Bcl11b/Ctip2 to be a key regulator in the development and function of the dentate gyrus, as well as the hippocampal mossy fiber system. We identified in this project a novel Bcl11b/Ctip2-C1ql2-Nrxn3(25b+)-dependent regulatory mechanism that is essential for the control of mossy fiber CA3 synapse function. Recent genetic studies, including our research, suggest that every single component of this regulatory pathway is associated with neurodevelopmental and neuropsychiatric disorders characterized by synaptic dysfunction. Our data, for the first time, demonstrate these molecules to be interconnected in one regulatory pathway. Thus, our findings not only clarify basic mechanisms in the establishment and maintenance of specific synaptic connections, but also provide new mechanistic insight into the pathogenesis of corresponding human disorders.
Publications
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Ex Utero Electroporation and Organotypic Slice Culture of Mouse Hippocampal Tissue. Journal of Visualized Experiments, 97
Venkataramanappa, Sathish; Simon, Ruth & Britsch, Stefan
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Structure‐function integrity of the adult hippocampus depends on the transcription factor Bcl11b/Ctip2. Genes, Brain and Behavior, 15(4), 405-419.
Simon, R.; Baumann, L.; Fischer, J.; Seigfried, F. A.; De Bruyckere, E.; Liu, P.; Jenkins, N. A.; Copeland, N. G.; Schwegler, H. & Britsch, S.
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BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells. Brain, 141(8), 2299-2311.
Lessel, Davor; Gehbauer, Christina; Bramswig, Nuria C; Schluth-Bolard, Caroline; Venkataramanappa, Sathish; van Gassen, Koen L I; Hempel, Maja; Haack, Tobias B; Baresic, Anja; Genetti, Casie A; Funari, Mariana F A; Lessel, Ivana; Kuhlmann, Leonie; Simon, Ruth; Liu, Pentao; Denecke, Jonas; Kuechler, Alma; de Kruijff, Ineke; Shoukier, Moneef; ... & Kubisch, Christian
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Stability and Function of Hippocampal Mossy Fiber Synapses Depend on Bcl11b/Ctip2. Frontiers in Molecular Neuroscience, 11(2018, 4, 5).
De Bruyckere, Elodie; Simon, Ruth; Nestel, Sigrun; Heimrich, Bernd; Kätzel, Dennis; Egorov, Alexei V.; Liu, Pentao; Jenkins, Nancy A.; Copeland, Neal G.; Schwegler, Herbert; Draguhn, Andreas & Britsch, Stefan
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Bcl11 Transcription Factors Regulate Cortical Development and Function. Frontiers in Molecular Neuroscience, 13(2020, 4, 8).
Simon, Ruth; Wiegreffe, Christoph & Britsch, Stefan
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Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway. (2024, 1, 23). Wallstein Verlag.
Koumoundourou, Artemis; Rannap, Märt; Bruyckere, Elodie De; Nestel, Sigrun; Reißner, Carsten; Egorov, Alexei V.; Liu, Pentao; Missler, Markus; Heimrich, Bernd; Draguhn, Andreas & Britsch, Stefan
