Involvement of BTBD1 in mesenchymal differentiation

Abstract

BTBD1 is a recently cloned BTB-domain-containing protein particularly expressed in skeletal muscle and interacting with DNA topoisomerase 1 (Topo1), a key enzyme of cell survival. We have previously demonstrated that stable overexpression of a N-terminal truncated BTBD1 inhibited ex vivo myogenesis but not adipogenesis of pluripotent C2C12 cells. Here, BTBD1 expression was studied in three models of cellular differentiation: myogenesis (C2C12 cells), adipogenesis (3T3-L1 cells) and osteogenesis (hMADS cells). BTBD1 mRNA was found to be upregulated during myogenesis. At the opposite, we have not observed BTBD1 upregulation in an altered myogenesis cellular model and we observed a downregulation of BTBD1 mRNA expression in adipogenesis. Interestingly, amounts of Topo1 protein, but not Topo1 mRNA, were found to be modulated at the opposite of BTBD1 mRNA. No variation of BTBD1 expression was measured during osteogenesis. Taken together, these results indicate that BTBD1 mRNA is specifically regulated during myogenic and adipogenic differentiation, in relation with Topo1 expression. Moreover, they corroborate observations made previously with truncated BTBD1 and show that BTBD1 is a key protein of balance between adipogenesis and myogenesis. Finally, a transcriptome analysis gave molecular clues to decipher BTBD1 role, with an emphasis on the involvement in ubiquitin/proteasome degradation pathway.

Identification of dosage‐sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia

“…BNC1 is involved in cell proliferation, and defective cell proliferation and migration in the PPFs of the developing diaphragm have been proposed to underlie CDH . Given the musculature of the diaphragm, BTBD1 is an interesting candidate involved in myoblast growth and differentiation …”

“…12 Given the musculature of the diaphragm, BTBD1 is an interesting candidate involved in myoblast growth and differentiation. 65,66 16p11.2 deletions can cause isolated CDH Deletions of 16p11.2 are a risk factor for autism. These deletions were recently reported in 2/45 cases of CDH.…”

Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond-Blackfan anaemia

“…Since the diaphragm is a muscular organ, it is possible that disruption of the BTB (POZ) domain containing 1 ( BTBD1 ) gene, which is essential for myoblast growth and differentiation in vitro, could play a role in development of CDH. [10] However, studies in rodent models suggest that some types of CDH arise from defects in the non-muscular mesenchymal substratum onto which myogenic cells and axons destined to form the neuromuscular component of the diaphragm expand. [11] Further studies have shown that development of posterolateral CDH can be associated with decreased cell proliferation leading to abnormal development of the pleuroperitoneal fold (PPF)—a triangular-shaped embryonic structure which represents the primordial diaphragm.…”

Btbd6-dependent Plzf recruitment to Cul3 E3 ligase complexes through BTB domain heterodimerization

“…Vertebrate genomes contain four genes of this BTB-BACK-PHR family: Btbd1-3 and Btbd6. Several studies have found potential substrates for members of this family [15,18,19], but little is known regarding the function or structural basis of the interactions. In our previous work, a yeast two-hybrid screen for proteins that bind Btbd6 identified both Cul3 and a transcriptional repressor protein, Plzf [15].…”