The functional impact of adult-generated granule cells in the epileptic brain is unclear, with data supporting both protective and maladaptive roles. These conflicting findings could be explained if new granule cells integrate heterogeneously, with some cells taking neutral or adaptive roles and others contributing to recurrent circuitry supporting seizures. Here, we tested this hypothesis by completing detailed morphological characterizations of age-and experience-defined cohorts of adult-generated granule cells from transgenic mice. The majority of newborn cells exposed to an epileptogenic insult exhibited reductions in dendritic spine number, suggesting reduced excitatory input to these cells. A significant subset, however, exhibited higher spine numbers. These latter cells tended to have enlarged cell bodies, long basal dendrites, or both. Moreover, cells with basal dendrites received significantly more recurrent mossy fiber input through their apical dendrites, indicating that these cells are robustly integrated into the pathological circuitry of the epileptic brain. These data imply that newborn cells play complex-and potentially conflicting-roles in epilepsy.

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Rapid accumulating evidence has suggested that the homeodomain transcription factors of the Nkx family play important roles in controlling vertebrate organ patterning and differentiation. In this study, we report the cloning, expression and regulation of a novel chicken homeobox gene, cNkx‐6.2, whose expression is similar, but not identical, to that of mouse Nkx‐6.2. The earliest expression of cNkx‐6.2 was detected at the neural plate stage in the prospective midbrain and hindbrain regions. As the neural development proceeds, cNkx‐6.2 expression was restricted in the ventral region of the entire neural axis except the forebrain region. At late stages of development, cNkx‐6.2 expression is downregulated in the ventricular neuroepithelial cells, but subsequently upregulated in a subpopulation of cells. Tissue recombination and explant culture experiments demonstrated that expression of cNkx‐6.2 can be induced by the notochord signal and purified SHH protein, and repressed by BMP‐4 and ‐7, indicating that the cNkx‐6.2 expression can be influenced by both ventral and dorsal midline signals. Taken together, these studies have suggested two different roles for the cNkx‐6.2 transcription factor: participating in the Shh‐initiated ventral patterning during early CNS development and controlling cell fate specification and differentiation during late development. Dev Dyn 1999;216:459–468. ©1999 Wiley‐Liss, Inc.

Lung cancer is the leading cause of cancer mortality in the United States and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein-1 (AP-1) transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study, we show induction of AP-1 in carcinogen-induced mouse lung tumors compared with surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant-negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared with lowergrade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis, and identify AP-1-dependent transcription as a potential target to prevent lung tumor progression. Cancer Prev Res; 3(9); 1148-56. ©2010 AACR.