An MLL-dependent network sustains hematopoiesis.

The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.

Neonatal maternal separation increases brain-derived neurotrophic factor and tyrosine kinase receptor B expression in the descending pain modulatory system.

Neonatal maternal separation (NMS) could trigger long-term changes in the central neuronal responses to nociceptive stimuli in rats. Stress-induced visceral hyperalgesia is closely associated with the dysfunction of descending pain modulatory systems. Brain-derived neurotrophic factor (BDNF) not only has an important role in long-term synaptic plasticity but also in facilitating descending pain. The present study aimed to investigate changes in the expression of BDNF and its receptor tyrosine kinase receptor B (TrkB) in the amygdala and the rostral ventromedial medulla (RVM) after NMS and colorectal distention (CRD) stimulation in rats. Male Wistar rat pups were subjected to 180 min of daily NMS or not handled for 13 consecutive days. Expression of BDNF and TrkB following NMS and CRD stimulation was determined using immunohistochemistry. The results revealed an increase in the expression of BDNF and TrkB in the amygdala after NMS. An interactive effect of NMS and CRD on the expression of TrkB, but not BDNF, was found in the RVM. Furthermore, a significant interactive effect of NMS and CRD on the colocalization coefficient of TrkB and phospho-extracellular signal-regulated kinase expression in both the amygdala and RVM were found. These data demonstrate that NMS increases BDNF and TrkB expression in the descending pain systems, which may contribute to the development of NMS-induced visceral hyperalgesia.

Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat.

Psychological stress experienced in early life plays an important role in the development of visceral hyperalgesia in irritable bowel syndrome (IBS). Neonatal maternal separation has been shown to trigger a long-term alternation in stress-induced responses to visceral nociceptive stimuli in rats. The aim of the present study was to show a direct evidence of stress-induced alteration in central neuronal responses to colorectal distention (CRD) in rats by a quantitative study of c-fos expression in relevant brain structures. Male Wistar rat pups were subjected to 180-min daily neonatal maternal separation (NMS) for 13 consecutive days (from PND 2 to PND 14). The expression of c-fos was examined by using immunohistochemistry. Increased c-fos expression was observed, for the first time, in the cingulate cortex (3-fold) in NMS rats in comparison with the control group at basal condition. At noxious CRD (80 mm Hg), c-fos expression was induced in the supraspinal centers and in both the superficial (laminae I-II) and the deeper laminae (laminae V-VI and X) of the spinal cord in rats. Significantly more Fos-IR nuclei were found in the laminae I and II, and laminae V-VI of the lumbarsacral spinal cord, the paraventricular thalamic nucleus, the cingulate cortex, the amygdaloid central nucleus in NMS rats, but not in the solitary tract, the central medial thalamic nucleus, the ventromedial hypothalamic nucleus, and the periaquaductal gray. The present results indicate that NMS has sensitized the cingulate cortex and upregulated the activity of the ascending pathway at spinal level as well as the thalamo-cortico-amydala pathway to CRD. The upregulation and sensitization of these pathways may be responsible for the development of visceral hypersensitivity in IBS.