MTA1 (metastasis-associated protein 1), an integral component of the nucleosome remodeling and deacetylase complex, has recently been implicated in the ionizing radiation-induced DNA damage response. However, whether MTA1 also participates in the UV-induced DNA damage checkpoint pathway remains unknown. In response to UV radiation, ATR (ataxia teleangiectasia-and Rad3-related) is the major kinase activated that orchestrates cell cycle progression with DNA repair machinery by phosphorylating and activating a number of downstream substrates, such as Chk1 (checkpoint kinase 1) and H2AX (histone 2A variant X). Here, we report that UV radiation stabilizes MTA1 in an ATR-dependent manner and increases MTA1 binding to ATR. On the other hand, depletion of MTA1 compromises the ATR-mediated Chk1 activation following UV treatment, accompanied by a marked down-regulation of Chk1 and its interacting partner Claspin, an adaptor protein that is required for the phosphorylation and activation of Chk1 by ATR. Furthermore, MTA1 deficiency decreases the induction of phosphorylated H2AX (referred to as ␥-H2AX) and ␥-H2AX focus formation after UV treatment. Consequently, depletion of MTA1 results in a defect in the G 2 -M checkpoint and increases cellular sensitivity to UV-induced DNA damage. Thus, MTA1 is required for the activation of the ATR-Claspin-Chk1 and ATR-H2AX pathways following UV treatment, and the noted abrogation of the DNA damage checkpoint in the MTA1-depleted cells may be, at least in part, a consequence of dysregulation of the expression of these two pathways. These findings suggest that, in addition to its role in the repair of double strand breaks caused by ionizing radiation, MTA1 also participates in the UV-induced ATR-mediated DNA damage checkpoint pathway.MTA1 (metastasis-associated protein 1), the founding member of the MTA 2 family, is widely up-regulated in human cancers and plays an important role in tumorigenesis, tumor invasion, and metastasis (1-3). As a dual function coregulator (3, 4), MTA1 functions not only as a transcriptional repressor of estrogen receptor-␣ (5), BRCA1 (breast cancer type 1 susceptibility protein) (6), Six3 (7), and p21 WAF11 (8) genes but also as a transcriptional activator via interacting with RNA polymerase II on the BCAS3 (breast cancer-amplified sequence 3) (9) and Pax5 (paired box gene 5) (10) promoters. The co-repressor versus co-activator activity of MTA1 might be influenced by its binding partners on the promoter region of various genes. In addition to its paramount role in cancer and coregulator biology, emerging evidence suggests that MTA1 is a DNA damageresponsive protein and facilitates DNA double strand break (DSB) repair following ionizing radiation (IR) treatment (11,12). In support of these findings, recent studies have demonstrated that MTA1 regulates p53-dependent and -independent DNA repair processes following IR treatment by modulating p53-p53R2 and p21 WAF1 -proliferating cell nuclear antigen pathways, respectively (8, 13). However, the new functions and rel...

Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability.

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Motor neurons are commonly thought of as mere relays between the central nervous system and the movement apparatus, yet, in mammals about one-third of them function exclusively as regulators of muscle proprioception. How these gamma motor neurons acquire properties to function differently from the muscle force-producing alpha motor neurons remains unclear. Here, we found that upon selective loss of the orphan nuclear receptors Err2 and Err3 (Err2/3) in mice, gamma motor neurons acquire characteristic structural (e.g. synaptic wiring), but not functional (e.g. physiological firing rates) properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements in vivo. Moreover, Err2/3 operate via transcriptional activation of neural activity modulators, one of which (Kcna10) promoted gamma motor neuron functional properties. Our work identifies a long-sought mechanism specifying gamma motor neuron properties necessary for proprioceptive movement control, which implies a feature-specific terminal differentiation program implementing neuron subtype-specific functional but not structural properties.