Progress and perspective of TBX6 gene in congenital vertebral malformations

Abstract

Congenital vertebral malformation is a series of significant health problems affecting a large number of populations. It may present as an isolated condition or as a part of an underlying syndromes occurring with other malformations and/or clinical features. Disruption of the genesis of paraxial mesoderm, somites or axial bones can result in spinal deformity. In the course of somitogenesis, the segmentation clock and the wavefront are the leading factors during the entire process in which TBX6 gene plays an important role. TBX6 is a member of the T-box gene family, and its important pathogenicity in spinal deformity has been confirmed. Several TBX6 gene variants and novel pathogenic mechanisms have been recently revealed, and will likely have significant impact in understanding the genetic basis for CVM. In this review, we describe the role which TBX6 plays during human spine development including its interaction with other key elements during the process of somitogenesis. We then systematically review the association between TBX6 gene variants and CVM associated phenotypes, highlighting an important and emerging role for TBX6 and human malformations.

Keywords: TBX6; congenital scoliosis; congenital vertebral malformation; somitogenesis; vertebrate segmentation.

Figure 1. The three main pathways with related genes and effectors in the somitogenesis

The clock (red frame)-wavefront (blue frame) model and components are shown. The clock is mainly consisted of Notch pathway and series of genes and effectors. Dll1 and its downstream NICD and Lfng expressed periodically through a feed-back loop to form the “clock” model. FGF and WNT signal gradients constitute the wavefront. In the Wnt pathway, Wnt3a induces the expression of downstream β-cat and the Axin2. The AXIN2 and DKK1 proteins are both negative-feedback inhibitors of β-cat, thereby forming a cyclical change. Wnt3a induces the expression of Tbx6, which further activates the expression of Dll1 and connects with NICD through Hes7, thus establishing communication rapport of Notch and WNT pathway. In the FGF pathway, Fgf4 and Ff8 genes induce the expression of pERK, which further prompts the expression of downstream Dusp4 and Dusp6. The FGF signal oscillation is also based on a feed-back mechanism.

Figure 2. The process of vertebrate segmentation and the interaction of the related genes

In the process of vertebrate segmentation, Tbx6, Mesp2 and downstream Ripply1/2 are important genes involved in somite segmentation. Tbx6 stimulated by the Wnt and FGF pathway signaling, later induces the expression of NICD (also induced by Notch signal) and Mesp2. Mesp2 initially expressed in a restricted area (one segment length), later with the Ripply1/2, (a feed-back inhibitor to Tbx6 and Mesp2) expression in the posterior half region, which defines the future segment boundaries.