The plasticity of aging suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and aging has mostly focused on histone deacetylation by the Sir2 family1,2, but less is known about the role of other histone modifications in longevity. Histone methylation plays a crucial role during development and in maintaining stem cell pluripotency in mammals3. Regulators of histone methylation have been associated with aging in worms4,5,6,7 and flies8, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex9, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in C. elegans in a directed RNAi screen in fertile worms. Deficiencies in members of the ASH-2 complex–ASH-2 itself, WDR-5, and the H3K4 methyltransferase SET-2 extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation–a mark associated with active chromatin–is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results suggest that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.

Boundary cap (BC) cells are neural crest derivatives that form clusters at the surface of the neural tube, at entry and exit points of peripheral nerve roots. Using various knock-in alleles of the mouse gene Egr2 (also known as Krox20), the expression of which, in trunk regions, is initially restricted to BC cells, we were able to trace BC cell progeny during development and analyze their fate. Trunk BC-derived cells migrated along peripheral axons and colonized spinal nerve roots and dorsal root ganglia (DRG). All Schwann cell precursors occupying the dorsal roots were derived from BC cells. In the DRG, BC-derived cells were the progenitors of both neurons, mainly nociceptive afferents, and satellite cells. These data indicate that BC cells constitute a source of peripheral nervous system (PNS) components that, after the major neural crest ventrolateral migratory stream, feeds a secondary wave of migration to the PNS.

The molecules involved in vertebrate tendon formation during development remain largely unknown. To date, only two DNA-binding proteins have been identified as being involved in vertebrate tendon formation, the basic helix-loop-helix transcription factor Scleraxis and, recently, the Mohawk homeobox gene. We investigated the involvement of the early growth response transcription factors Egr1 and Egr2 in vertebrate tendon formation. We established that Egr1 and Egr2 expression in tendon cells was correlated with the increase of collagen expression during tendon cell differentiation in embryonic limbs. Vertebrate tendon differentiation relies on a muscle-derived FGF (fibroblast growth factor) signal. FGF4 was able to activate the expression of Egr genes and that of the tendon-associated collagens in chick limbs. Egr gene misexpression experiments using the chick model allowed us to establish that either Egr gene has the ability to induce de novo expression of the reference tendon marker scleraxis, the main tendon collagen Col1a1, and other tendon-associated collagens Col3a1, Col5a1, Col12a1, and Col14a1. Mouse mutants for Egr1 or Egr2 displayed reduced amounts of Col1a1 transcripts and a decrease in the number of collagen fibrils in embryonic tendons. Moreover, EGR1 and EGR2 trans-activated the mouse Col1a1 proximal promoter and were recruited to the tendon regulatory regions of this promoter. These results identify EGRs as novel DNA-binding proteins involved in vertebrate tendon differentiation by regulating type I collagen production.Vertebrate tendons are specialized dense connective tissues mainly composed of collagens that connect muscle to bone.Tendon repair following injuries or during aging is a clinical challenge because tendons are only repaired slowly and partially. The establishment of new strategies for tendon repair is prevented by a limited understanding of tendon development and consequently awaits a better understanding of tendon development. An important goal is to understand the molecular mechanisms involved in regulating collagen expression, production, and assembly during tendon development to be able to design new therapies for tendon repair.Tendons consist of elongated fibroblasts named tenocytes that produce an abundant extracellular matrix composed of Ͼ90% collagen. The major collagen component of mature tendon is type I collagen, a heterotrimeric molecule composed of two ␣1 chains and one ␣2 chain that are genetically distinct and encoded by Col1a1 and Col1a2, respectively (1-3). Type I collagen molecules self-assemble into highly organized parallel collagen fibrils and then into fibers, which provide the tensile strength of tendon. Other collagens, such as the fibrillar collagens III and V and the nonfibrillar collagens named FACITs (fibril-associated collagens with interrupted triple helices), and collagens XII and XIV are important for collagen fibril formation, growth, and integrity of tendons. In addition to collagens, tendons contain various matrix components contributing to the prop...

Spinal motor neurons must extend their axons into the periphery through motor exit points (MEPs), but their cell bodies remain within spinal motor columns. It is not known how this partitioning is established in development. We show here that motor neuron somata are confined to the CNS by interactions with a neural crest subpopulation, boundary cap (BC) cells that prefigure the sites of spinal MEPs. Elimination of BC cells by surgical or targeted genetic ablation does not perturb motor axon outgrowth but results in motor neuron somata migrating out of the spinal cord by translocating along their axons. Heterologous neural crest grafts in crest-ablated embryos stop motor neuron emigration. Thus, before the formation of a mature transitional zone at the MEP, BC cells maintain a cell-tight boundary that allows motor axons to cross but blocks neuron migration.