Abstract
TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in the modulation of important cellular pathways and master regulators of transcriptional output, including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in a neurological context, leaving a knowledge gap in the mechanisms at the basis of the diseases. Here, we show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1 or its point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to a failure in the regulation of the MAPK cascade. Taken together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
Highlights
The building of a healthy nervous system is due to a concerted array of molecular mechanisms within and between different cell types during the embryonic life and beyond (Borrell, 2019)
We show that the genetic knock-out of Tbl1xr1 in mice leads to behavioral impairments that, to a certain extent, are similar to those typical of human patients mutated in the same gene
We demonstrated that Tbl1xr1 mutant brain exhibits morphological and functional alterations originated by an increased proliferation and delayed differentiation of neural stem cells of the embryonic brain
Summary
The building of a healthy nervous system is due to a concerted array of molecular mechanisms within and between different cell types during the embryonic life and beyond (Borrell, 2019). TBL1XR1, encoding for transducin β-like 1—related protein 1 (a member of HDAC containing NCOR/SMRT complexes) (Yoon et al, 2003), has been associated with different human developmental diseases, spanning from autism spectrum disorders (ASD) (O’Roak et al, 2012; Stessman et al, 2017), to West syndrome (Saitsu et al, 2014), schizophrenia (SCZ) (Nishi et al, 2017), intellectual disability (Pons et al, 2015; Riehmer et al, 2017). Mutations leading to the substitution Y446C of TBL1XR1 are the only genetic cause of Pierpont syndrome. To our knowledge the hypothesis that mutations in TBL1XR1 gene directly lead to neurological impairment— and whether this is due to the disruption of the function of NCOR complex—has not been investigated in high systems (e.g., mammals)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
