Sox2 transcriptionally regulates PQBP1, an intellectual disability-microcephaly causative gene, in neural stem progenitor cells

Chan Li; Hikaru Ito; Kyota Fujita; Hiroki Shiwaku; Yunlong Qi; Kazuhiko Tagawa; Takuya Tamura; Hitoshi Okazawa

doi:10.1371/journal.pone.0068627

Sox2 transcriptionally regulates PQBP1, an intellectual disability-microcephaly causative gene, in neural stem progenitor cells

PLoS One. 2013 Jul 16;8(7):e68627. doi: 10.1371/journal.pone.0068627. Print 2013.

Authors

Chan Li¹, Hikaru Ito, Kyota Fujita, Hiroki Shiwaku, Yunlong Qi, Kazuhiko Tagawa, Takuya Tamura, Hitoshi Okazawa

Affiliation

¹ Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Abstract

PQBP1 is a nuclear-cytoplasmic shuttling protein that is engaged in RNA metabolism and transcription. In mouse embryonic brain, our previous in situ hybridization study revealed that PQBP1 mRNA was dominantly expressed in the periventricular zone region where neural stem progenitor cells (NSPCs) are located. Because the expression patterns in NSPCs are related to the symptoms of intellectual disability and microcephaly in PQBP1 gene-mutated patients, we investigated the transcriptional regulation of PQBP1 by NSPC-specific transcription factors. We selected 132 genome sequences that matched the consensus sequence for the binding of Sox2 and POU transcription factors upstream and downstream of the mouse PQBP1 gene. We then screened the binding affinity of these sequences to Sox2-Pax6 or Sox2-Brn2 with gel mobility shift assays and found 18 genome sequences that interacted with the NSPC-specific transcription factors. Some of these sequences had cis-regulatory activities in Luciferase assays and in utero electroporation into NSPCs. Furthermore we found decreased levels of expression of PQBP1 protein in NSPCs of heterozygous Sox2-knockout mice in vivo by immunohistochemistry and western blot analysis. Collectively, these results indicated that Sox2 regulated the transcription of PQBP1 in NSPCs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Carrier Proteins / genetics
Carrier Proteins / metabolism*
DNA-Binding Proteins
Electrophoretic Mobility Shift Assay
Eye Proteins / genetics
Eye Proteins / metabolism
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Immunohistochemistry
Mice
Mice, Knockout
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neural Stem Cells / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
PAX6 Transcription Factor
POU Domain Factors / genetics
POU Domain Factors / metabolism
Paired Box Transcription Factors / genetics
Paired Box Transcription Factors / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism*

Substances

Carrier Proteins
DNA-Binding Proteins
Eye Proteins
Homeodomain Proteins
Nerve Tissue Proteins
Nuclear Proteins
PAX6 Transcription Factor
POU Domain Factors
Paired Box Transcription Factors
Pax6 protein, mouse
Pqbp1 protein, mouse
Repressor Proteins
SOXB1 Transcription Factors
Sox2 protein, mouse
Pou3f2 protein, mouse

Grants and funding

This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (Foundation of Synapse and Neurocircuit Pathology) and Strategic Research Program for Brain Sciences (SRPBS) from Ministry of Education, Culture, Sports, Science and Technology of Japan, to HO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.