H. R. Russell

An Infrared Survey of Brightest Cluster Galaxies. II. Why are Some Brightest Cluster Galaxies Forming Stars

Quillen et al. presented an imaging survey with the Spitzer Space Telescope of 62 brightest cluster galaxies with optical line emission located in the cores of X-ray-luminous clusters. They found that at least half of these sources have signs of excess IR emission. Here we discuss the nature of the IR emission and its implications for cool core clusters. The strength of the mid-IR excess emission correlates with the luminosity of the optical emission lines. Excluding the four systems dominated by an AGN, the excess mid-IR emission in the remaining brightest cluster galaxies is likely related to star formation. The mass of molecular gas (estimated from CO observations) is correlated with the IR luminosity as found for normal star-forming galaxies. The gas depletion timescale is about 1 Gyr. The physical extent of the IR excess is consistent with that of the optical emission-line nebulae. This supports the hypothesis that star formation occurs in molecular gas associated with the emission-line nebulae and with evidence that the emission-line nebulae are mainly powered by ongoing star formation. We find a correlation between mass deposition rates () estimated from the X-ray emission and the star formation rates estimated from the IR luminosity. The star formation rates are 1/10 to 1/100 of the mass deposition rates, suggesting that the reheating of the intracluster medium is generally very effective in reducing the amount of mass cooling from the hot phase but not eliminating it completely.

Loss of suppressor-of-fused function promotes tumorigenesis

The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/− mice, Sufu+/− mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/− animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/−p53−/− animals resulted from Sufu loss of heterozygosity. Sufu+/−p53−/− medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.

TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo.

Defective Tyrosyl‐DNA phosphodiesterase 1 (TDP1) can cause spinocerebellar ataxia with axonal neuropathy (SCAN1), a neurodegenerative syndrome associated with marked cerebellar atrophy and peripheral neuropathy. Although SCAN1 lymphoblastoid cells show pronounced defects in the repair of chromosomal single‐strand breaks (SSBs), it is unknown if this DNA repair activity is important for neurons or for preventing neurodegeneration. Therefore, we generated Tdp1−/− mice to assess the role of Tdp1 in the nervous system. Using both in vitro and in vivo assays, we found that cerebellar neurons or primary astrocytes derived from Tdp1−/− mice display an inability to rapidly repair DNA SSBs associated with Top1–DNA complexes or oxidative damage. Moreover, loss of Tdp1 resulted in age‐dependent and progressive cerebellar atrophy. Tdp1−/− mice treated with topotecan, a drug that increases levels of Top1–DNA complexes, also demonstrated significant loss of intestinal and hematopoietic progenitor cells. These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1‐associated DNA strand breaks.

DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair

DNA replication and repair in mammalian cells involves three distinct DNA ligases: ligase I (Lig1), ligase III (Lig3) and ligase IV (Lig4). Lig3 is considered a key ligase during base excision repair because its stability depends upon its nuclear binding partner Xrcc1, a critical factor for this DNA repair pathway. Lig3 is also present in the mitochondria, where its role in mitochondrial DNA (mtDNA) maintenance is independent of Xrcc1 (ref. 4). However, the biological role of Lig3 is unclear as inactivation of murine Lig3 results in early embryonic lethality. Here we report that Lig3 is essential for mtDNA integrity but dispensable for nuclear DNA repair. Inactivation of Lig3 in the mouse nervous system resulted in mtDNA loss leading to profound mitochondrial dysfunction, disruption of cellular homeostasis and incapacitating ataxia. Similarly, inactivation of Lig3 in cardiac muscle resulted in mitochondrial dysfunction and defective heart-pump function leading to heart failure. However, Lig3 inactivation did not result in nuclear DNA repair deficiency, indicating essential DNA repair functions of Xrcc1 can occur in the absence of Lig3. Instead, we found that Lig1 was critical for DNA repair, but acted in a cooperative manner with Lig3. Additionally, Lig3 deficiency did not recapitulate the hallmark features of neural Xrcc1 inactivation such as DNA damage-induced cerebellar interneuron loss, further underscoring functional separation of these DNA repair factors. Therefore, our data reveal that the critical biological role of Lig3 is to maintain mtDNA integrity and not Xrcc1-dependent DNA repair.

Patched2 modulates tumorigenesis in patched1 heterozygous mice.

The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis. Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man. In many cases, medulloblastoma arising from perturbations of Ptch1 function leads to a concomitant up-regulation of a highly similar gene, Patched2 (Ptch2). As increased expression of Ptch2 is associated with medulloblastoma and other tumors, we investigated the role of Ptch2 in tumor suppression by generating Ptch2-deficient mice. In striking contrast to Ptch1-/- mice, Ptch2-/- animals were born alive and showed no obvious defects and were not cancer prone. However, loss of Ptch2 markedly affected tumor formation in combination with Ptch1 haploinsufficiency. Ptch1+/-Ptch2-/- and Ptch1+/-Ptch2+/- animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with Ptch1+/- animals. Therefore, Ptch2 modulates tumorigenesis associated with Ptch1 haploinsufficiency.

Chandra observation of two shock fronts in the merging galaxy cluster Abell 2146

We present a new Chandraobservation of the galaxy cluster Abell 2146 which has revealed a complex merging system with a gas structure that is remarkably similar to the Bullet cluster (eg. Markevitch et al. 2002). The X-ray image and temperature map show a cool 2− 3 keV subcluster with a ram pressure stripped tail of gas just exit ing the disrupted 6− 7 keV primary cluster. From the sharp jump in the temperature and density of the gas, we determine that the subcluster is preceded by a bow shock with a Mach number M = 2.2� 0.8, corresponding to a velocity v = 2200 +1000 −900 km s −1 relative to the main cluster. We estimate that the subcluste r passed through the primary core only 0.1− 0.3 Gyr ago. In addition, we observe a slower upstream shock propagating through the outer region of the primary cluster and calculate a Mach number M = 1.7� 0.3. Based on the measured shock Mach numbers M � 2 and the strength of the upstream shock, we argue that the mass ratio between the two merging clusters is between 3 and 4 to one. By comparing the Chandra observation with an archival HST observation, we find that a group of galaxies is located in fro nt of the X-ray subcluster core but the brightest cluster galaxy is located immediately behind the X-ray peak.

Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS

The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.

The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1

Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.

The Reaper-Binding Protein Scythe Modulates Apoptosis and Proliferation during Mammalian Development

ABSTRACT Scythe (BAT3 [HLA-B-associated transcript 3]) is a nuclear protein that has been implicated in apoptosis, as it can modulate Reaper, a central apoptotic regulator in Drosophila melanogaster. While Scythe can markedly affect Reaper-dependent apoptosis in Xenopus laevis cell extracts, the function of Scythe in mammals is unknown. Here, we report that inactivation of Scythe in the mouse results in lethality associated with pronounced developmental defects in the lung, kidney, and brain. In all cases, these developmental defects were associated with dysregulation of apoptosis and cellular proliferation. Scythe− / − cells were also more resistant to apoptosis induced by menadione and thapsigargin. These data show that Scythe is critical for viability and normal development, probably via regulation of programmed cell death and cellular proliferation.

Deep high-resolution X-ray spectra from cool-core clusters

We examine deep XMM-Newton Reflection Grating Spectrometer (RGS) spectra from the cores of three X-ray bright cool-core galaxy clusters, Abell 262, Abell 3581 and HCG 62. Each of the RGS spectra shows Fe XVII emission lines indicating the presence of gas around 0.5 keV. There is no evidence for O VII emission which would imply gas at still cooler temperatures. The range in detected gas temperature in these objects is a factor of 3.7, 5.6 and 2 for Abell 262, Abell 3581 and HCG 62, respectively. The coolest detected gas only has a volume filling fraction of 6 and 3 per cent for Abell 262 and Abell 3581, but is likely to be volume filling in HCG 62. Chandra spatially resolved spectroscopy confirms the low volume filling fractions of the cool gas in Abell 262 and Abell 3581, indicating this cool gas exists as cold blobs. Any volume heating mechanism aiming to prevent cooling would overheat the surroundings of the cool gas by a factor of 4. If the gas is radiatively cooling below 0.5 keV, it is cooling at a rate at least an order of magnitude below that at higher temperatures in Abell 262 and Abell 3581 and two orders of magnitude lower in HCG 62. The gas may be cooling non-radiatively through mixing in these cool blobs, where the energy released by cooling is emitted in the infrared. We find very good agreement between smooth particle inference modelling of the cluster and conventional spectral fitting. Comparing the temperature distribution from this analysis with that expected in a cooling flow, there appears to be an even larger break below 0.5 keV as compared with previous empirical descriptions of the deviations of cooling flow models.