The regular spacing of somites during vertebrate embryogenesis involves a dynamic gradient of FGF signaling that controls the timing of maturation of cells in the presomitic mesoderm (PSM). How the FGF signal is transduced by PSM cells is unclear. Here, we first show that the FGF gradient is translated into graded activation of the extracellular signal-regulated kinase (ERK)͞mitogen-activated protein kinase (MAPK) pathway along the PSM in the chicken embryo. Using in ovo electroporation of PSM cells, we demonstrate that constitutive activation of ERK signaling in the PSM blocks segmentation by preventing maturation of PSM cells, thus phenocopying the overexpression of FGF8. Conversely, inhibition of ERK phosphorylation mimics a loss of function of FGF signaling in the PSM. Interestingly, video microscopy analysis of cell movements shows that ERK regulates the motility of PSM cells, suggesting that the decrease of cell movements along the PSM enables mesenchymal PSM cells to undergo proper segmentation. Together, our data demonstrate that ERK is the effector of the gradient of FGF in the PSM that controls the segmentation process. extracellular signal-regulated kinase ͉ fibroblast growth factor ͉ somite S omitogenesis leads to the subdivision of the paraxial mesoderm into transient epithelial metameric units, called somites (1). Somite formation begins anteriorly and proceeds posteriorly, passing like a wave through the paraxial mesoderm as successive groups of cells segregate from the PSM at regular intervals, in concert with extension of the body axis (2). Somite formation involves an oscillator (the segmentation clock) that drives cyclic gene expression. This periodic signal is converted into the repeated array of somite boundaries by a spacing mechanism relying on a traveling threshold of FGF8 and Wnt3a that regresses with body axis extension (3). FGF8 mRNA and protein are distributed in a graded fashion in the caudal presomitic mesoderm (PSM) of vertebrate embryos (4-6), and overexpression of FGF8 in the PSM cells prevents them from differentiating (5). These data led to the idea that high concentrations of FGF8 are required to actively maintain newly formed PSM cells in an immature state. Thus, because of the progressive decrease of FGF8 expression during maturation of the PSM, cells reach a threshold of FGF signaling at a given level in the PSM, called the ''determination front'', where they activate their segmentation program. This determination front marks a molecular transition for PSM cells, as shown by the down-regulation of posterior genes such as brachyury and the activation of new sets of genes such as paraxis in the anterior PSM (5). In chick and fish embryos, FGFR1 is the only FGF receptor to be expressed in the PSM, and in mouse, the FGFR1 knockout disrupts somite formation, suggesting that FGFR1 mediates FGF8 activity in somitogenesis (4,5,7,8).FGF signaling activates a variety of downstream effectors, such has mitogen-activated protein kinase (MAPK)͞extracellu-lar signal-regulated kinase (ERK)...

C-low-threshold mechanoreceptors (C-LTMRs) are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs. Genetic labeling in combination with electrophysiological recordings show that TAFA4+ neurons have intrinsic properties of mechano-nociceptors. TAFA4-null mice exhibit enhanced mechanical and chemical hypersensitivity following inflammation and nerve injury as well as increased excitability of spinal cord lamina IIi neurons, which could be reversed by intrathecal or bath application of recombinant TAFA4 protein. In wild-type C57/Bl6 mice, intrathecal administration of TAFA4 strongly reversed carrageenan-induced mechanical hypersensitivity, suggesting a potent analgesic role of TAFA4 in pain relief. Our data provide insights into how C-LTMR-derived TAFA4 modulates neuronal excitability and controls the threshold of somatic sensation.

Hox protein function during development and evolution relies on conserved multiple interaction modes with cofactors of the PBC and Meis families.