In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by rhombomere 3-derived neurons, whereas the rhombomere 2-derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and rhombomere 3-dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.

NCCs retain a remarkable degree of plasticity even after their migration in the arch, and require Hoxa2 as an integral component of their morphogenetic program. Moreover, subpopulations of postmigratory NCCs required Hoxa2 at discrete time points to pattern distinct derivatives. This study provides the first temporal inactivation of a vertebrate Hox gene and illustrates Hox requirement during late morphogenetic processes.

Circular RNAs (circRNAs) are a new class of noncoding singlestranded RNAs that differ from linear microRNAs (miRNAs), since they form covalently closed loop structures without free 3 0 poly(A) tails or 5 0 caps. circRNAs are the competitive endogenous RNAs (ceRNAs) by binding to miRNA through miRNA response elements (MREs) (i.e., "miRNA sponge"), thereby reducing the quantity of miRNA available to target mRNA, subsequently promoting mRNA stability or protein expression, which involves the initiation and progress of human diseases. Owing to these features of abundance, stability, conservative property, and tissue and stage specificity, widely distributing in the extracellular space and in various bodily fluids, circRNAs can be considered as potential biomarkers for various diseases. Here, we reviewed the promising circRNAs being disease biomarkers, focused on their regulatory function by acting as miRNA sponges, and described their roles in cancer, cardiovascular or neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, diabetes, and other human aging-related diseases, which provide a new direction for pathogenesis, diagnosis, and treatment of human aging-related diseases.Circular RNAs (circRNAs) are a new class of noncoding singlestranded RNA, 1 characterized by covalently closed loop structures without free 3 0 poly(A) tails or 5 0 caps. These features differentiate them from linear RNAs, 2 long noncoding RNAs (lncRNAs), and mi-croRNAs (miRNAs). 3 Although circRNAs were first discovered in the 1990s in viruses, viroids, and tetrahymena, 4 little attention has been paid to their function. 4,5 At that time, they were considered abnormal products, resulting from splicing errors. 3,6 In addition, circRNAs are often found in low abundance, and the traditional methods used to study linear RNAs are not applicable. With recent developments in biochemical-enrichment methods, especially high-throughput RNA sequencing and circRNAs microarray, more than 30,000 circRNAs have been discovered. 7 They are widely expressed in yeasts, plants, protists, fruit flies, worms, zebrafish, mice, rats, and humans. 8 Compared with the levels of their linear isomers, circRNA expression levels can be increased by 10-fold or more, 9 an indication of their potential abundance. Owing to their distinctive structure, they can resist exonuclease activity and are extremely stable. 1 The average lifetime of a 3 0 / 5 0 -linked circRNA is 2$5 times longer than that of a linear mRNA. 1 In addition, the expression levels of circRNAs are tissue and stage specific, and a number of highly abundant circRNAs have been found to exist in human peripheral blood (PB), 10 indicating that circRNAs can act as biomarkers to screen, diagnose, characterize, and monitor various diseases. circRNAs have many biological functions, including regulating host gene splicing and transcription, 11 acting as miRNA 12 and protein sponges, 8 reacting with proteins, 13 and serving as protein-coding circRNAs. 14 Many studies [15][16][17] have indicated that circRNAs con...

Chronic myeloid leukemia chronic phase (CML-CP) CD34 ؉ cells contain numerous DNA double-strand breaks whose unfaithful repair may contribute to chromosomal instability and disease progression to blast phase (CML-BP). These phenomena are often associated with the appearance of imatinib-resistant BCR-ABL1 kinase mutants (eg, T315I) and overexpression of BCR-ABL1. Here we show that BCR-ABL1 (nonmutated and T315I mutant) promoted RAD51 recombinase-mediated unfaithful homeologous recombination repair (HomeoRR) in a dosage-dependent manner. BCR-ABL1 SH3 domain interacts with RAD51 proline-rich regions, resulting in direct phosphorylation of RAD51 on Y315 (pY315). RAD51(pY315) facilitates dissociation from the complex with BCR-ABL1 kinase, migrates to the nucleus, and enhances formation of the nuclear foci indicative of recombination sites. HomeoRR and RAD51 nuclear foci were strongly reduced by RAD51(Y315F) phosphorylationless mutant. In addition, peptide aptamer mimicking RAD51(pY315) fragment, but not that with Y315F phosphorylation-less substitution, diminished RAD51 foci formation and inhibited HomeoRR in leukemia cells. In conclusion, we postulate that BCR-ABL1 kinase-mediated RAD51(pY315) promotes unfaithful HomeoRR in leukemia cells, which may contribute to accumulation of secondary chromosomal aberrations responsible for CML relapse and progression. (Blood. 2011;118(4):1062-1068) IntroductionChronic myeloid leukemia in chronic phase (CML-CP) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome that results from a (9;22)(q34;q11) reciprocal translocation that juxtaposes the c-abl oncogene 1 (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22, generating the BCR-ABL1 fusion oncogene. Most CML-CP patients are currently treated with tyrosine kinase inhibitor (TKI) imatinib designed to block the enzymatic action of the ABL1 tyrosine kinase. Approximately 60%-70% of patients achieve and maintain a complete cytogenetic response (CCyR) 5 years after initiating imatinib treatment. Two "second-generation" TKIs, dasatinib and nilotinib, are effective at inducing or restoring CCyR in 40%-50% of patients who appear to have failed primary treatment with imatinib. However approximately 20% of patients presenting with CML-CP fail to respond to both imatinib and a subsequent second-generation TKI; their prognosis is poor because of a higher risk of disease progression. In addition, because TKIs do not eradicate the disease, the patients in CCyR may carry 10 6 to 10 9 leukemia cells, and even BCR-ABL1-negative patients in complete molecular response may have up to 10 6 leukemia cells. 1 These cells may be the "time-ticking bombs" eventually exploding into TKI-resistant clone and/or CML-blast phase (CML-BP) clone on accumulation of additional genetic aberrations. 2 Clinical observations and experimental findings clearly demonstrated that genomic instability in CML is driven, at least in part, by BCR-ABL1 kinase. 2,3 However, TKI-treated CML pat...

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Recent studies indicated that retention of selectable marker cassettes in targeted Hox loci may cause unexpected phenotypes in mutant mice, due to neighborhood effects. However, the molecular mechanisms have been poorly investigated. Here, we analysed the effects of the targeted insertion of a PGK-neo cassette in the 3 untranslated region of Hoxa2. Even at this 3 position, the insertion resulted in homozygous mutants that unexpectedly did not survive beyond 3 weeks of age. Molecular analysis of the targeted allele revealed a selective "knockdown" of Hoxa2 expression in rhombomere 2 and associated patterning abnormalities. Moreover, Hoxa1 was ectopically expressed in the hindbrain and branchial arches of mutant embryos. Of interest, we demonstrated that the ectopic expression was due to the generation of neo-Hoxa1 fusion transcripts, resulting from aberrant alternative splicing. These defects could be rescued after removal of the PGK-neo cassette by Flp-mediated recombination. These results underscore the complexity of transcriptional regulation at Hox loci and provide insights into the in vivo regulation of Hoxa2 segmental expression. They also provide a molecular basis for the interpretation of unexpected Hox knockout phenotypes in which the targeted selectable marker is retained in the locus.

Objective: Liquid-based cytology of nongynecological specimens is commonly used in cytology laboratories throughout the world and various processing methods, such as ThinPrep and SurePath, have been reported. The cytological features and performance of liquid-based cytology for various cytology specimens, including body cavity fluids, urine, brushing specimens and fine-needle aspiration of various lesions, were reviewed and compared with the experience of our laboratory and the literature published in PubMed. Study Design: The parameters for the evaluation of liquid-based cytology and conventional smears were described in the various types of specimens. Criteria for the interpretation of nongynecological liquid-based cytology were highlighted to show differences in cell morphology, background and artifacts. Results: The interpretation requires familiarity with the appearance of liquid-based cytology in the various types of preparations to avoid misdiagnosis. Conclusions: Cell blocks can be prepared with specimens preserved in a liquid-based cytology medium and immunocytochemical stains and molecular testing can be successfully performed. These are important adjuncts in order to reach a definitive diagnosis.