Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines.

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of Kras;Pik3ca or Trp53 and/or ablation of Pten or Trp53. We find that Kras;Pik3ca is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions.

The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis.

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs.

The atypical CDK activator RingoA/Spy1 regulates exit from quiescence in neural stem cells.

In the adult mammalian brain, most neural stem cells (NSCs) are held in a reversible state of quiescence, which is essential to avoid NSC exhaustion and determine the appropriate neurogenesis rate. NSCs of the mouse adult subependymal niche provide neurons for olfactory circuits and can be found at different depths of quiescence, but very little is known on how their quiescence-to-activation transition is controlled. Here, we identify the atypical cyclin-dependent kinase (CDK) activator RingoA as a regulator of this process.

Differential requirements for Tousled-like kinases 1 and 2 in mammalian development.

The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type.

GEMC1 is a critical regulator of multiciliated cell differentiation.

The generation of multiciliated cells (MCCs) is required for the proper function of many tissues, including the respiratory tract, brain, and germline. Defects in MCC development have been demonstrated to cause a subclass of mucociliary clearance disorders termed reduced generation of multiple motile cilia (RGMC). To date, only two genes, Multicilin (MCIDAS) and cyclin O (CCNO) have been identified in this disorder in humans.

Hepatic overexpression of a constitutively active form of liver glycogen synthase improves glucose homeostasis.

In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state.

Tissue selective expression of conditionally-regulated ROCK by gene targeting to a defined locus.

ROCK kinases regulate actin-myosin structures downstream of Rho GTPases. We generated mice expressing 4-hydroxytamoxifen (4HT)-regulated human ROCK II (ROCKII:mER) under the transcriptional control of the cytokeratin14 (K14) promoter. The K14-ROCKII:mER minigene was recombineered into a novel cloning vector containing the promoter and first exon of the human HPRT gene, and second and third exons of the mouse Hprt gene.

The effects of a mutant connexin 26 on epidermal differentiation.

To elucidate the mode of action of dominant mutant connexins in causing inherited skin diseases, transgenic mice were produced that express the true Vohwinkel syndrome-associated mutant Cx26 (D66H), from a keratin 10 promoter, specifically in the suprabasal epidermal keratinocytes. Following birth, the transgenic mice developed keratoderma similar to that of human carriers of Cx26 (D66H). Expression of the transgene resulted in a loss of Cx26 and Cx30 at intercellular junctions of epidermal keratinocytes and accumulation of these connexins in the cytoplasm.

Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders.

To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm.