Molecular clocks underlying vertebrate embryo segmentation: A 10‐year‐old hairy‐go‐round

Abstract

Segmentation of the vertebrate embryo body is a fundamental developmental process that occurs with strict temporal precision. Temporal control of this process is achieved through molecular segmentation clocks, evidenced by oscillations of gene expression in the unsegmented presomitic mesoderm (PSM, precursor tissue of the axial skeleton) and in the distal limb mesenchyme (limb chondrogenic precursor cells). The first segmentation clock gene, hairy1, was identified in the chick embryo PSM in 1997. Ten years later, chick hairy2 expression unveils a molecular clock operating during limb development. This review revisits vertebrate embryo segmentation with special emphasis on the current knowledge on somitogenesis and limb molecular clocks. A compilation of human congenital disorders that may arise from deregulated embryo clock mechanisms is presented here, in an attempt to reconcile different sources of information regarding vertebrate embryo development. Challenging open questions concerning the somitogenesis clock are presented and discussed, such as When?, Where?, How?, and What for? Hopefully the next decade will be equally rich in answers.

Sonic hedgehog in temporal control of somite formation

“…Multiple congenital vertebral malformations have been associated with mutations in somitogenesis clock genes (1,3). Furthermore, there are reports associating the Shh signaling pathway with congenital vertebral anomalies (27,28).…”

“…In the trunk of the chicken embryo, a pair of somites is formed every 90 min from the anterior tip of presomitic mesoderm (PSM). As development proceeds, ventral somitic cells migrate around the axial organs, giving rise to segmented structures such as vertebrae, intervertebral disks, and ribs, whereas more dorsal somitic cells give rise to the dermis of the back and all of the striated muscles of the adult body (1). Underlying somitogenesis periodicity is a molecular clock first evidenced by the cyclic expression of hairy1 in chick PSM cells with 90-min periodicity, corresponding to the time of somite formation (2).…”

“…Underlying somitogenesis periodicity is a molecular clock first evidenced by the cyclic expression of hairy1 in chick PSM cells with 90-min periodicity, corresponding to the time of somite formation (2). Currently, multiple genes belonging to Notch, Wnt, and Fgf signaling pathways are known to have similar oscillatory behavior and to participate in the embryo segmentation clock (1,3). Posterior PSM cells in an undetermined state are influenced by high FGF/ Wnt levels, which fade away anteriorly, counteracted by an opposing gradient of RA (4)(5)(6).…”

Portuguese contributions to the discovery and characterization of the embryonic molecular clock

“…This fact suggests the existence of an internal clock-like machinery controlling both the rhythm and duration of somitogenesis, in a species-specific manner (reviewed by Freitas et al, 2005;Andrade et al, 2005Andrade et al, , 2007. In fact, the existence of such a cellular clock had been suggested about 30 years ago by Cooke and Zeeman in a theoretical model named "The clock and wavefront model" (Cooke and Zeeman, 1976).…”

Symmetry OUT, Asymmetry IN

“…After epithelialization from the anterior region of the PSM, each somite undergoes a dorsal-ventral compartmentalization so that the ventral region, enclosing the sclerotome, is different from the dorsal region, the dermomyotome. This subdivision is important for later patterning events, with the sclerotome differentiating into the axial skeleton and ribs, and the dermomyotome giving rise to the dermis of the back and skeletal muscles [104]. A diverse number of human conditions associated with vertebral malformations arise as a consequence of mutations in important somitogenesis-related genes.…”