Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT.

The conservation of developmental functions exerted by Antpclass homeoproteins in protostomes and deuterostomes suggested that homologs with related functions are present in diploblastic animals. Our phylogenetic analyses showed that Antp-class homeodomains belong either to non-Hox or to Hox͞paraHox families. Among the 13 non-Hox families, 9 have diploblastic homologs, Msx, Emx, Barx, Evx, Tlx, NK-2, and Prh͞Hex, Not, and Dlx, reported here. Among the Hox͞paraHox, poriferan sequences were not found, and the cnidarian sequences formed at least five distinct cnox families. Two are significantly related to the paraHox Gsx (cnox-2) and the mox (cnox-5) sequences, whereas three display some relatedness to the Hox paralog groups 1 (cnox-1), 9͞10 (cnox-3) and the paraHox cdx (cnox-4). Intermediate Hox͞paraHox genes (PG 3 to 8 and lox) did not have clear cnidarian counterparts. In Hydra, cnox-1, cnox-2, and cnox-3 were not found chromosomally linked within a 150-kb range and displayed specific expression patterns in the adult head. During regeneration, cnox-1 was expressed as an early gene whatever the polarity, whereas cnox-2 was up-regulated later during head but not foot regeneration. Finally, cnox-3 expression was reestablished in the adult head once it was fully formed. These results suggest that the Hydra genes related to anterior Hox͞paraHox genes are involved at different stages of apical differentiation. However, the positional information defining the oral͞aboral axis in Hydra cannot be correlated strictly to that characterizing the anterior-posterior axis in vertebrates or arthropods. T he discovery of structural and functional homologies between regulatory genes used by Drosophila and vertebrates during their development led to the hypothesis that animals would share a common set of genes for defining the head, trunk, and posterior regions at early developmental stages (1-6). The proposed genes were homeobox genes belonging either to the Antp class, like empty-spiracle (emx), even-skipped (evx), Hox genes, or to the Prd class, like orthodenticle (Otx), goosecoid. Phylogenetic analyses performed on a vast amount of Hox homeodomain (HD) sequences, including representatives from all classes of homeobox genes from animals, protozoa, fungi, and plants, confirmed the monophyly of the Antp class as well as its position as a sister group to the Paired class (7). Within the Antp class, the Hox gene organization is distinctive and enigmatic: the genes map in clusters, and the order of individual genes within a cluster correlates with their temporospatial expression pattern along the anterior-posterior body axis during development (8). Recently, it was proposed that the common bilaterian ancestor of protostomes and deuterostomes had at least seven Hox genes (9). However, the question of the composition of the ancestral HOX cluster remains open. Analysis of Hox homeobox sequences (10) suggested that the conserved HOX cluster emerged early in the evolution of metazoans from an original cluster harboring three ancestral g...

Hydra regenerate throughout their life. We previously described early modulations in cAMP-response element-binding protein (CREB) DNA-binding activity during regeneration. We now show that the Ser-67 residue located in the P-box is a target for posttranslational regulation. The antihydra CREB antiserum detected CREB-positive nuclei distributed in endoderm and ectoderm, whereas the phosphoSer133-CREB antibody detected phospho-CREB-positive nuclei exclusively in endodermal cells. During early regeneration, we observed a dramatic increase in the number of phospho-CREB-positive nuclei in head-regenerating tips, exceeding 80% of the endodermal cells. We identified among CREBbinding kinases the p80 kinase, which showed an enhanced activity and a hyperphosphorylated status during head but not foot regeneration. According to biochemical and immunological evidence, this p80 kinase belongs to the Ribosomal protein S6 kinase family. Exposure to the U0126 mitogen-activated protein kinase kinase inhibitor inhibited head but not foot regeneration, abolished CREB phosphorylation and activation of the early gene HyBra1 in head-regenerating tips. These data support a role for the mitogen-activated protein kinase͞ribosomal protein S6 kinase͞ CREB pathway in hydra head organizer activity. S pecies that display regenerative capacities can be found in most animal phyla, from invertebrates to vertebrates, likely representing an ancestral feature lost several times during evolution. The central issue concerning regeneration is the unfolding of developmental programs in adult tissues, ending ultimately in a de novo morphogenesis. That issue is poorly understood, but some stages might rely on conserved ancestral mechanisms. Hydra, which belong to the Cnidaria phylum, a sister group to bilaterians, bud and regenerate throughout their life. Hence their developmental programs stay permanently accessible. Hydra are made up of two cell layers, ectoderm and endoderm, separated by the mesoglea. After midgastric section, regeneration of the missing part is achieved within 3 days, resulting from differentiation of cells from the gastric region in the absence of cell proliferation during the first day.Although early modulations in gene expression have been identified during regeneration (see ref. 1), little is known about the signaling mechanisms that control regeneration (2, 3). Diacylglycerol treatment induces formation of multiple heads (4), whereas inhibition of PKC and mitogen-activated protein kinase (MAPK) pathways selectively block head regeneration and initiation of budding (5-7). In hydra, conserved regulatory elements have been tested in gel retardation assays, and a significant modulation during both apical and basal regeneration was detected with the cAMP response element (CRE). The hydra CRE-binding protein (CREB) gene was cloned, showing a high level of similarity with vertebrate cognate genes (8, 9). In vertebrates, CREB mediates the response to a large array of extracellular signals to the nucleus through posttranslational modifi...