Dissecting the roles of miR-140 and its host gene

Dissecting the roles of miR-140 and its host gene

To the editor

The functional coherence between microRNAs (miRNAs) and their host genes remains enigmatic. As host genes and their intron-derived miRNAs are transcribed as cistronic units, their functional coherence could be beneficial for the organism. Indeed, several intronic miRNAs are reported to act coherently with their host genes for processes such as muscle fibre-type selection or cholesterol metabolism1,2. However, it is not clear how broadly that coherence takes place in an organism. Previously, we and others have reported that targeted deletion of a chondrocyte-specific miRNA, miR-140, caused craniofacial truncation due to impaired chondrocyte differentiation3,4. miR-140 regulates several target genes, including Adamts-5 and Dnpep, and in turn governs the proliferation and differentiation of chondrocytes3,4. Interestingly, ubiquitin E3 ligase Wwp2, the host gene of miR-140, knockout (KO) mice were subsequently reported in Nature Cell Biology (Wwp2GT/GT mouse) with a similar craniofacial truncation phenotype5. In this report, Zou et al. demonstrated that Wwp2 mono-ubiquitylates the transcription factor Goosecoid, and this modification is indispensable for transcription of Sox6 (a key transcription factor for chondrocyte differentiation) and thus Wwp2GT/GT mice displayed the craniofacial phenotype due to cartilage malformation5. These reports suggested an intriguing possibility that miR-140 and its host gene, Wwp2, have overlapping or coherent functions in craniofacial morphogenesis. At the same time, the methodology to generate the Wwp2GT allele — insertion of a gene-trap cassette into the third intron of the Wwp2 gene5 — attracted our attention. The gene-trap cassette prevents expression of exons and introns downstream of its insertion site, and indeed Zou et al. showed that the Wwp2 transcript that corresponded to downstream exons were absent from their KO mice5. As such, miR-140, which is encoded further downstream, might also be downregulated in these mice. In this scenario, the craniofacial phenotype observed in Wwp2GT/GT mice might be, in part, caused by the loss of miR-140.

Journal Article

Nature Cell Biology

Induced Proton Perturbation for Sensitive and Selective Detection of Tight Junction Breakdown


Correspondence to

Hiroshi ASAHARA,M.D., Ph.D., Professor
Department of Systems BioMedicine,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)