The subdivision of the paraxial mesoderm into somites, a metameric series of homologous subunits, is the most obvious sign of segmentation in early vertebrate embryos. During mouse embryogenesis, the first somites form in the posterior headfold region of the embryo around embryonic day 7.75 (E7.75). Subsequently, new somites condense at regular intervals in a strict anteriorto-posterior sequence from the unsegmented so-called presomitic mesoderm (psm) that lies caudally to the first somites. Somite condensation progresses while concomitantly new paraxial mesoderm cells are being generated caudally from the primitive streak and later from the tail bud elongating the embryo posteriorly.Somite formation is coupled to a molecular oscillator referred to as the segmentation clock, which has been revealed by the cyclic expression of genes in the psm. Expression of cyclic genes is periodic such that one wave of expression passes through the psm during the formation of one somite (Palmeirim et al. 1997;Forsberg et al. 1998;Jiang et al. 2000;Jouve et al. 2000;Aulehla et al. 2003). The segmentation clock is closely linked to Notch and WNT signaling activity. Most genes displaying cyclic activity encode components of the Notch pathway (Palmeirim et al. 1997;Forsberg et al. 1998;Jiang et al. 2000;Jouve et al. 2000); one other cyclic gene encodes the WNT pathway component Axin2 (Aulehla et al. 2003). Altered Notch signaling disrupts somite formation and patterning in Xenopus, zebrafish, and mouse embryos (Conlon et al. 1995;Hrabe de Angelis et al. 1997;Jen et al. 1999;Holley et al. 2000;Jiang et al. 2000;Sawada et al. 2000). Furthermore, mutations in some Notch pathway components, which lead to defects in somitogenesis, also affect the expression of cyclic genes (del Barco Barrantes et al. 1999;Jiang et al. 2000;Jouve et al. 2000;Dunwoodie et al. 2002), indicating that Notch signaling is essential for generating cyclic gene expression. Cyclic Lfng gene expression was shown in chick and mouse embryos to be essential for Lfng function (Dale et al. 2003;Serth et al. 2003). Disruption of WNT/ ␤-catenin signaling also affects somitogenesis and cyclic expression of Notch pathway components, whereas cyclic Axin2 expression is maintained when Notch signaling is impaired (Aulehla et al. 2003;Aulehla and Herrmann 2004), suggesting that WNT acts upstream of Notch in the segmentation clock. However, the exact molecular interplay between the various components of these pathways is not fully understood.T-box transcription factors as well as FGF and WNT signaling are essential regulators of formation and differentiation or maintenance of paraxial mesoderm in mouse embryos. Mutations in T, Fgfr1, Wnt3a, and Tbx6 cause defects in formation and differentiation of paraxial mesoderm. Loss of T gene function leads to failure of axis development and arrested somite formation (Wilkinson et al. 1990; Herrmann 1995) most likely because of impaired migration of mesodermal cells through the primitive streak (Wilson et al. 1993). The loss of Wnt3a also ...

Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

Rib-vertebrae (rv) is an autosomal recessive mutation in mouse that affects somite formation, morphology, and patterning. Expression of Notch pathway components is affected in the paraxial mesoderm of rv mutant embryos, and rv and a null allele of the Notch ligand delta1 show non-allelic non-complementation. By fine genetic mapping and complementation testing we have identified Tbx6, a gene essential for paraxial mesoderm formation, as the gene mutated in rv. Compound heterozygotes carrying a Tbx6 null allele and rv show a phenotype that is milder than in homozygous Tbx6 null but more severe than in homozygous rv mutants. Tbx6 expression is down-regulated in rv mutant embryos. An insertion in the promoter region upstream of the transcriptional start is present in the genome of rv mutants but not in different strains of mice wild type for Tbx6. Our results indicate that rv is a regulatory mutation of Tbx6 causing a hypomorphic phenotype.

Atrophy of the olfactory epithelium (OE) associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging) on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc−/−) with short telomeres compared to wild type mice (mTerc+/+) with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc−/− mice compared to mTerc+/+ mice. Seven days after chemical induced damage, G3 mTerc−/− mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc+/+ mice (p = 0.031). Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21) rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.

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