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A number of vertebrate genes of the Dlx gene family have been cloned in mouse, frog, and zebrafish. These genes contain a homeobox related to that of Distalless, a gene expressed in the developing head and limbs of Drosophila embryos. We cloned and studied the expression of two members of this family, which we amaed DlxS and Dax6, in human and mouse. The two human genes, DLXS and DLX6, are closely linked in an inverted convergent configuration in a region of chromosome 7, at 7q22. Similarly, the two human genes DLXI and DLK2 are closely linked in a convergent configuration at 2q32, near the HOXD (previously HOX4) locus. In situ hybridization experiments in mouse embryos revealed expression of DlxS and Dlx6 mRNA in restricted regions of ventral diencephalon and basal teencephalon, with a distribution very similar to that reported forDMl and Dx2 mRNA. A surprising feature of DlxS and Dlx6 is that they are also expressed in all skeletal sutures of dtion embryos after the first cartilae formation. The expreion pattern of these genes, together with their chromosome calation, may provide useftl cues for the study of congenital disorders in which there is a combination of cranlofacial and limb defects.Many vertebrate genes have been identified by virtue of their nucleotide sequence similarity with Drosophila developmental genes. Many homeobox-containing genes (1) have been identified on this basis. The Dlx gene family (2-7) has been identified because these genes contain a homeobox related to that of Distalless (Dli, also known as Ba) a gene expressed in the head and limbs of the developing fruit fly (8-9).Cloned Dlx sequences in the mouse (2-4), frog (6, 7), and zebrafish (5) have been shown to correspond to at least four different genes, Dlxi-Dlx4. A detailed expression analysis has been carried out for murine Dlxi (2, 10, 11) and Dlx2 (3, 4, 12) genes. They appear to be expressed within the central nervous system of midgestation mouse embryos in specific regions ofthe forebrain, but not in more posterior parts of the neural tube. In early embryos they are also expressed in branchial arches, in the otic vesicle, and in facial and limb primordia. Expression in the developing inner ear has been also reported (5) for the zebrafish cognate of Dlx3. With the notable exception of Xdli2 (7), several frog genes (Xenopus) of the Dlx family have been identified (6, 7) that are similarly expressed in the anterior portion of the embryonic neural tube. In many instances, a correlation of their expression domain with forebrain regionalization (13,14) has been suggested (2)(3)(4)(5)(6)(7)(10)(11)(12) MATERIALS AND METHODSExpression Analysis. A cDNA library prepared from 8-week human embryos (15) was screened at low-stringency conditions with a short Dli genomic sequence including the homeobox (8). Four classes of homologous cDNA clones, corresponding to DLX), DLX2, DLX5, and DLX6, were found. Using these cDNA clones as probes, we screened in turn a human genomic library constructed in cosmids (15) to study the transcrip...

The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1-and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

We report the identification of 10 new human homeobox sequences. Altogether, we have isolated and sequenced 30 human homeoboxes clustered in 4 chromosomal regions called HOX loci. HOX1 includes 8 homeoboxes in 90 kb of DNA on chromosome 7. HOX2 includes 9 homeoboxes in 180 kb on chromosome 17. HOX3 contains at least 7 homeoboxes in 160 kb on chromosome 12. Finally, HOX4 includes 6 homeoboxes in 70 kb on chromosome 2. Homeodomains obtained from the conceptual translation of the isolated homeoboxes can be attributed to 13 homology groups on the basis of their primary peptide sequence. Moreover, it is possible to align the 4 HOX loci so that corresponding homeodomains in all loci share the maximal sequence identity. The complex of these observations supports and extends an evolutionary hypothesis concerning the origin of mammalian and fly homeobox gene complexes. We also determined the coding region present in 3 HOX2 cDNA clones corresponding to HOX2G, HOX2H and HOX2I.

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Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both −/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.