Forward genetics uncovers Transmembrane protein 107 as a novel factor required for ciliogenesis and Sonic hedgehog signaling

Abstract

Cilia are dynamic organelles that are essential for a vast array of developmental patterning events, including left-right specification, skeletal formation, neural development, and organogenesis. Despite recent advances in understanding cilia form and function, many key ciliogenesis components have yet to be identified. By using a forward genetics approach, we isolated a novel mutant allele (schlei) of the mouse Transmembrane protein 107 (Tmem107) gene, which we show here is critical for cilia formation and embryonic patterning. Tmem107 is required for normal Sonic hedgehog (Shh) signaling in the neural tube and acts in combination with Gli2 and Gli3 to pattern ventral and intermediate neuronal cell types. schlei mutants also form extra digits, and we demonstrate that Tmem107 acts in the Shh pathway to determine digit number, but not identity, by regulating a subset of Shh target genes. Phenotypically, schlei mutants share several features with other cilia mutants; however, spatial restriction of mutant phenotypes and lack of left-right patterning defects in schlei animals suggest differential requirements for Tmem107 in cilia formation in distinct tissues. Also, in contrast to mutants with complete loss of cilia, schlei mutants retain some function of both Gli activator and repressor forms. Together, these studies identify a previously unknown regulator of ciliogenesis and provide insight into how ciliary factors affect Shh signaling and cilia biogenesis in distinct tissues.

The usefulness of whole-exome sequencing in routine clinical practice

“…TMEM107 is a key component of the Sonic Hedgehog pathway and ciliogenesis, which are implicated in normal facial, oral, and acral development. 15 It is worth noting that the clinical laboratories reported new candidate disease genes in 18 cases. However, upon critical review of the literature, model organisms, and patients' phenotypic features, we considered only four of these to be viable new candidate genes.…”

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

“…One of these, the NPHP complex, is mostly involved in the ciliopathy nephronophthisis (NPHP) and includes Nphp1, Nphp4, and Rpgrip1l (Mollet et al 2005; Arts et al 2007; Sang et al 2011). A second complex, involved mostly in Meckel (MKS) and Joubert (JBTS) syndromes and referred to as the MKS complex, includes the three Tectonic proteins (Tctn1, 2, 3), the three B9 domain proteins (Mks1, B9d1, B9d2), the coiled-coil proteins Cc2d2a and Cep290, Ahi1 and the transmembrane proteins Tmem67, Tmem216, Tmem17, Tmem231, Tmem107, and possibly others such as Tmem237 and Tmem218 (Chih et al 2011; Garcia-Gonzalo et al 2011; Huang et al 2011; Sang et al 2011; Christopher et al 2012; Barker et al 2014; Roberson et al 2015; Lambacher et al 2016; Li et al 2016; Shylo et al 2016). …”

Cyclin-dependent Kinase 9 Links RNA Polymerase II Transcription to Processing of Ribosomal RNA

“…Instead, a major defect at the level of 3Ј end processing was observed (57). U8 snoRNA is embedded in the 3Ј-UTR of TMEM107 mRNA (58). Thus, 3Ј processing of U8 pre-snoRNA might also be inhibited in analogy to hsp70 pre-mRNA.…”