METTL3-mediated m^(6)A RNA methylation regulates dorsal lingual epithelium homeostasis

The dorsal lingual epithelium,which is composed of taste buds and keratinocytes differentiated from K14^(+)basal cells,discriminates taste compounds and maintains the epithelial barrier.N6-methyladenosine(m^(6)A)is the most abundant mRNA modification in eukaryotic cells.How METTL3-mediated m^(6)A modification regulates K14^(+)basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear.Here we show knockout of Mettl3 in K14^(+)cells reduced the taste buds and enhanced keratinocytes.Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds.Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization,but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery.Mechanically,we revealed that the most frequent m^(6)A modifications were enriched in Hippo and Wnt signaling,and specific peaks were observed near the stop codons of Lats1 and FZD7.Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.

Insights into skeletal stem cells

The tissue-resident skeletal stem cells(SSCs),which are self-renewal and multipotent,continuously provide cells(including chondrocytes,bone cells,marrow adipocytes,and stromal cells)for the development and homeostasis of the skeletal system.In recent decade,utilizing fluorescence-activated cell sorting,lineage tracing,and single-cell sequencing,studies have identified various types of SSCs,plotted the lineage commitment trajectory,and partially revealed their properties under physiological and pathological conditions.In this review,we retrospect to SSCs identification and functional studies.We discuss the principles and approaches to identify bona fide SSCs,highlighting pioneering findings that plot the lineage atlas of SSCs.The roles of SSCs and progenitors in long bone,craniofacial tissues,and periosteum are systematically discussed.We further focus on disputes and challenges in SSC research.

N6-methyladenosine(m6A)modification of ribosomal RNAs(rRNAs):Critical roles in mRNA translation and diseases

key components of the ribosome and the most abundant RNA species,the rRNAs are modified during ribosome formation.N^(6)-methyladenosine(m^(6)A)is a conserved RNA modification occurring on different RNA species including rRNAs.Recently,it has been reported that ZCCHC4 and METTL5 are methyltransferases that mediate m^(6)A modification of human 28S and 18S rRNA,respectively.The newly discovered biological functions of the two methyltransferases include regulation of mRNA translation,cell proliferation,cell differentiation,stress response,and other biological processes.Both of them,especially METTL5,have been proved to be associated with a variety of diseases such as intellectual disability,cancer,congenital dysplasia and have potential clinical application as biomarkers and therapeutic targets.

METTL5 regulates cranial suture fusion via Wnt signaling

METTL5 is a methyltransferase that mediates eukaryotic 18S ribosomal RNA m^(6)A modification,and its mutations lead to intellectual disability,microcephaly,and facial dysmorphism in patients.However,the role of METTL5 in craniofacial development remains poorly understood.This study demonstrates that Mettl5 knockout mice exhibit poor ossification,widened cranial sutures,and a cleidocranial dysplasia-like phenotype.Deletion of Mettl5 leads to increased proliferation and decreased osteogenic differentiation of suture mesenchymal stem cells.Mechanistically,we find that Wnt signaling is significantly downregulated after Mettl5 knockout.Overall,we reveal an essential role of METTL5 in craniofacial development and osteogenic differentiation of suture mesenchymal stem cells,making METTL5 a potential diagnostic and therapeutic target for craniofacial developmental diseases.