Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins.

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement1. These networks produce left–right alternation of limbs as well as coordinated activation of flexor and extensor muscles2. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl- 2 IntroductionMast cells are long-lived multifunctional effector cells of the immune system originating from the hematopoietic CD34 ϩ stem cells found in the bone marrow. 1 From the bone marrow, mast cell precursors enter the circulation where they are recruited into peripheral tissues to mature and express their final phenotype under the influence of stem cell factor (SCF) and other locally produced cytokines. 2 Although best known for their role in allergic reactions, mast cells are now also recognized as cells of importance in both innate immunity and in the onset and severity of chronic inflammations. 3,4 The versatile effector mechanisms mast cells have been endowed with can be deduced from their capability to release a wide variety of inflammatory mediators such as histamine, proteases, and cytokines that are preformed and stored in granules and prostaglandins, leukotrienes, and cytokines that are secreted upon activation. 5 The number of tissue mast cells is normally relatively constant, but during an acute or chronic inflammation the number can increase substantially. 6 The regulation of mast cell numbers is most likely regulated by proliferation, migration, and apoptosis or survival. The mechanisms that regulate the viability of mature mast cells or promote mast cell apoptosis are poorly investigated. SCF is a cardinal growth factor in mast cell biology, regulating mast cell growth, differentiation, adhesion, migration, and survival. 7 The number of tissue mast cells is at least in part regulated by SCF produced by resident stromal cells. SCF rescues mast cells from spontaneous apoptosis in vitro, whereas inhibition of SCF synthesis in vivo leads to mast cell apoptosis. [8][9][10] Although it is accepted that SCF is a prosurvival factor for mast cells, it remains largely unclear how SCF promotes survival in these cells.The B-cell lymphoma-2 (Bcl-2) family, which contains both prosurvival and proapoptotic proteins, are essential regulators of cell survival and apoptosis. 11 The levels and interactions of prosurvival versus proapoptotic Bcl-2 family proteins determine whether a cell survives or will undergo apoptosis. During apoptosis induced by proapoptotic Bcl-2 family members, cytochrome c is released from the mitochondria and a caspase cascade is activated that induces DNA fragmentation. 12,13 The prosurvival Bcl-2 family members include Bcl-2, Bcl-X L , Bcl-w, Mcl-1 (myeloid cell For personal use only. on May 12, 2018. by guest www.bloodjournal.org From leuk...