Altered Cogs of the Clock: Insights into the Embryonic Etiology of Spondylocostal Dysostosis

Abstract

Spondylocostal dysostosis (SCDO) is a rare heritable congenital condition, characterized by multiple severe malformations of the vertebrae and ribs. Great advances were made in the last decades at the clinical level, by identifying the genetic mutations underlying the different forms of the disease. These were matched by extraordinary findings in the Developmental Biology field, which elucidated the cellular and molecular mechanisms involved in embryo body segmentation into the precursors of the axial skeleton. Of particular relevance was the discovery of the somitogenesis molecular clock that controls the progression of somite boundary formation over time. An overview of these concepts is presented, including the evidence obtained from animal models on the embryonic origins of the mutant-dependent disease. Evidence of an environmental contribution to the severity of the disease is discussed. Finally, a brief reference is made to emerging in vitro models of human somitogenesis which are being employed to model the molecular and cellular events occurring in SCDO. These represent great promise for understanding this and other human diseases and for the development of more efficient therapeutic approaches.

Keywords: DLL3; HES7; LFNG; MESP2; RIPPLY2; TBX6; somite formation; somitogenesis clock; spondylocostal dysostosis.

Figure 1

Vertebral and rib malformations identified in different types of spondylocostal dysostosis (SCDO).

Figure 2

The Molecular Clock and Signaling Gradients in temporal/spatial control of vertebrate somitogenesis. (A) Representation of one oscillation of hairy1 gene expression (blue) in the presomitic mesoderm (PSM) of a 48h chicken embryo. A cell in the PSM (red dot) undergoes a complete cycle of gene expression activation-repression-activation as a new somite is formed in the anterior-most PSM. (B) Opposing gradients of retinoic acid (RA) and WNT/FGF signaling converge at the determination front; rostrally, the PSM tissue is already committed to form somites.

Figure 3

Negative feedback loops underlie somitogenesis clock oscillations. The identified mutated genes in SCDO are represented. Upon Notch receptor activation by a Delta ligand from a neighbor cell, the Notch intracellular domain (NICD) translocates to the nucleus where it activates the transcription of HES7, LFNG and DLL3 [23]. Lfng and Dll3 act cooperatively to repress further NICD activation [50], while Hes7 acts to represses its own expression and that of Lfng [23].

Figure 4

From somitogenesis clock oscillations to somite boundary formation. Periodic activation of Mesp2 at the rostral PSM, where FGF signaling is greatly decreased, triggers a molecular cascade ultimately leading to the budding off of a new somite. This is a simplified schematic representation, where the identified mutated genes in SCDO are highlighted.

Figure 5

Differentiation of the different somite regions into definitive axial structures. After budding off from the PSM as epithelial spheres, somite differentiation takes place distinguishing the prospective cell populations that will give rise to adult structures. Colors in the figure represent precursor cells in the somite (left) and their respective definitive structures (right).