The protein kinase MLTK regulates chondrogenesis by inducing the transcription factor Sox6

Abstract

SUMMARYSox9 acts together with Sox5 or Sox6 as a master regulator for chondrogenesis; however, the inter-relationship among these transcription factors remains unclear. Here, we show that the protein kinase MLTK plays an essential role in the onset of chondrogenesis through triggering the induction of Sox6 expression by Sox9. We find that knockdown of MLTK in Xenopus embryos results in drastic loss of craniofacial cartilages without defects in neural crest development. We also find that Sox6 is specifically induced during the onset of chondrogenesis, and that the Sox6 induction is inhibited by MLTK knockdown. Remarkably, Sox6 knockdown phenocopies MLTK knockdown. Moreover, we find that ectopic expression of MLTK induces Sox6 expression in a Sox9-dependent manner. Our data suggest that p38 and JNK pathways function downstream of MLTK during chondrogenesis. These results identify MLTK as a novel key regulator of chondrogenesis, and reveal its action mechanism in chondrocyte differentiation during embryonic development.

Sox5 Is a DNA-Binding Cofactor for BMP R-Smads that Directs Target Specificity during Patterning of the Early Ectoderm

“…Distinct from many NC regulatory factors, ectodermal expression of Sox5 is initially broad and low at early NC stages before becoming strongly enriched at the neural plate border (NPB) (Suzuki et al, 2012, Figure S1A-F). It is also maternally provided and expressed throughout the ectoderm at blastula stages (Figure S1G,H).…”

“…NC cells maintain expression of Sox5 as they begin to migrate, similar to what has been described in chick (Morales et al, 2007; Perez-Alcala et al, 2004). The closely related SoxD factor, Sox6, was not detected in early NC cells (Suzuki et al, 2012, Figure S1I). …”

“…The first, (BC142559), is encoded by an EST obtained from the I.M.A.G.E Consortium and is referred to here as Sox5*. A second Sox5 isoform (AB682776) with an extended c-terminus was subsequently reported (Suzuki et al, 2012). We confirmed via PCR that both forms are expressed in early Xenopus embryos and we have found no functional differences between them (Figure 1, Figure S3 and not shown).…”

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice

“…No role had been assigned to ZAK in vertebrate limb development, but knockdown of its Xenopus laevis ortholog mltk was previously shown to result in loss of craniofacial cartilage (Gotoh et al 2001;Suzuki et al 2012). ZAK was shown to be a direct target of TP63 binding, and a functional link of both proteins was suggested; ZAK has also been shown to suppress the JNK pathway (Yang et al 2006;Wang et al 2014a).…”

Overexpression of ZAKβ in human osteosarcoma cells enhances ZAKα expression, resulting in a synergistic apoptotic effect

“…6 ZAKα plays a kinase role, and it has been demonstrated that ZAKα can phosphorylate histone 3 at Ser 28 . 9 These studies have led many scientists to believe that ZAKα may play an oncogenic role in promoting tumour development. 8 ZAKα can also regulate chondrogenesis by inducing the transcription factor Sox6.…”