Abstract
Transcription factor 4 is a class I basic helix-loop-helix transcription factor regulating gene expression. Altered TCF4 gene expression has been linked to non-syndromic intellectual disability, schizophrenia, and a severe neurodevelopmental disorder known as Pitt-Hopkins syndrome. An understanding of the cell types expressing TCF4 protein in the mouse brain is needed to help identify potential pathophysiological mechanisms and targets for therapeutic delivery in TCF4-linked disorders. Here we developed a novel green fluorescent protein reporter mouse to visualize TCF4-expressing cells throughout the brain. Using this TCF4 reporter mouse, we observed prominent expression of TCF4 in the pallial region and cerebellum of the postnatal brain. At the cellular level, both glutamatergic and GABAergic neurons express TCF4 in the cortex and hippocampus, while only a subset of GABAergic interneurons express TCF4 in the striatum. Among glial cell groups, TCF4 is present in astrocytes and immature and mature oligodendrocytes. In the cerebellum, cells in the granule and molecular layer express TCF4. Our findings greatly extend our knowledge of the spatiotemporal and cell type-specific expression patterns of TCF4 in the brain, and hence, lay the groundwork to better understand TCF4-linked neurological disorders. Any effort to restore TCF4 functions through small molecule or genetic therapies should target these brain regions and cell groups to best recapitulate TCF4 expression patterns.
Highlights
Received: 20 April 2020 Accepted: 22 June 2020 Published: 17 July 2020Citation: Kim H, Berens NC, Ochandarena NE and Philpot BD (2020) Region and Cell Type Distribution of TCF4 in the PostnatalMouse Brain
The insertion of a 2A self-cleaving peptide (P2A) enables green fluorescent protein (GFP) molecules to freely diffuse throughout the cytoplasm, making it possible to track axonal projections from TCF4-expressing neurons, though at the cost of not being able to use it to identify the subcellular localization of TCF4
The band intensity of fulllength TCF4 was reduced by approximately half in lysates from Tcf4LGSL/+ compared to WT mice (Figure 1C: WT: 1.00 ± 0.02, n = 5; Het: 0.54 ± 0.03, n = 11; Homo: 0.00 ± 0.00, n = 3)
Summary
Received: 20 April 2020 Accepted: 22 June 2020 Published: 17 July 2020Mouse Brain. Front. Transcription factor 4 (TCF4, Gene ID 6925) is a basic helix-loop-helix (bHLH) transcription factor, acting as both a repressor and activator of gene expression (Massari and Murre, 2000). The protein’s functional domains include a first activation domain, a nuclear localization signal, a second activation domain, and a bHLH domain. The bHLH domain consists of a basic region that directly mediates DNA binding and amphipathic helices that provide a dimerization interface. TCF4 can form homo- and hetero-dimers with cell type-specific bHLH proteins, which modulate its function (Murre et al, 1994). The human TCF4 gene can be transcribed from multiple promoters, and the usage of alternative 5 exons and splicing produces protein isoforms with 18 different N -termini and variable functional domains (Sepp et al, 2011). Genomic alterations that affect TCF4 function or levels increase the risk of neurodevelopmental or psychiatric
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