Long-range migrating progenitor cells generate hypaxial muscle, for instance the muscle of the limbs, hypoglossal cord, and diaphragm. We show here that migrating muscle progenitors express the chemokine receptor CXCR4. The corresponding ligand, SDF1, is expressed in limb and branchial arch mesenchyme; i.e., along the routes and at the targets of the migratory cells. Ectopic application of SDF1 in the chick limb attracts muscle progenitor cells. In CXCR4 mutant mice, the number of muscle progenitors that colonize the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of the muscle progenitor cells were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but also control survival. Gab1 encodes an adaptor protein that transduces signals elicited by tyrosine kinase receptors, for instance the c-Met receptor, and plays a role in the migration of muscle progenitor cells. We found that CXCR4 and Gab1 interact genetically. For instance, muscle progenitors do not reach the anlage of the tongue in CXCR4;Gab1 double mutants; this target is colonized in either of the single mutants. Our analysis reveals a role of SDF1/CXCR4 signaling in the development of migrating muscle progenitors and shows that a threshold number of progenitor cells is required to generate muscle of appropriate size.[Keywords: CXCR4; Gab1; hypaxial muscle; migration] Supplemental material is available at http://www.genesdev.org.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

In the developing muscle, a pool of myogenic progenitor cells is formed and maintained. These resident progenitors provide a source of cells for muscle growth in development and generate satellite cells in the perinatal period. By the use of conditional mutagenesis in mice, we demonstrate here that the major mediator of Notch signaling, the transcription factor RBP-J, is essential to maintain this pool of progenitor cells in an undifferentiated state. In the absence of RBP-J, these cells undergo uncontrolled myogenic differentiation, leading to a depletion of the progenitor pool. This results in a lack of muscle growth in development and severe muscle hypotrophy. In addition, satellite cells are not formed late in fetal development in conditional RBP-J mutant mice. We conclude that RBP-J is required in the developing muscle to set aside proliferating progenitors and satellite cells.yogenesis is a tightly regulated process that is essential in muscle development and regeneration. During mammalian development, phases of embryonic and fetal myogenic differentiation lead to the formation and growth of skeletal muscles. In the postnatal and adult organism, skeletal muscle grows and regenerates by the myogenic differentiation of stem cells, the satellite cells (1). Muscle progenitor cells during development or satellite cells in the adult initiate myogenic differentiation as a result of the activation of myogenic determination factors like Myf5 and MyoD and form myoblasts (for reviews, see refs. 2-4). Mononucleated myoblasts begin to express muscle-specific proteins and fuse to form multinucleated myotubes, the constituents of mature skeletal muscle.Skeletal muscle and satellite cells of the body and the extremities derive from the somites, segmental derivatives of the paraxial mesoderm (5-10). As the somite matures, myogenic progenitor cells become confined to the dermomyotome that expresses the transcription factor Pax3 (paired box protein 3). After myogenesis is initiated, a resident progenitor population that expresses Pax3 and Pax7 is maintained in the developing muscle (7-9). Late in fetal development, the progenitor population generates satellite cells, which are marked by the expression of Pax7 (7-9). Some, but not all, satellite cells also express Pax3 (11). Thus, in a developing or adult muscle, a pool of undifferentiated cells is preserved that has the potential to undergo myogenic differentiation. The molecular mechanism used to set aside this population of progenitor cells is not understood.The Notch signaling pathway is highly conserved in evolution and plays important roles during development and in the adult. Notch signals regulate diverse processes, including maintenance of progenitors, cell fate decisions, proliferation, and differentiation (for reviews, see refs. 12-14). Notch signaling is initiated by the interaction of the Notch receptor (Notch 1-4 in mammals) with its ligand (Delta-like 1, 3, and 4 and Jagged 1 and 2 in mammals). Ligand binding results in proteolytic cleavage of the receptor and ...

Distinct types of relay neurons in the hindbrain process somatosensory or viscerosensory information. How neurons choose between these two fates is unclear. We show here that the homeobox gene Lbx1 is essential for imposing a somatosensory fate on relay neurons in the hindbrain. In Lbx1 mutant mice, viscerosensory relay neurons are specified at the expense of somatosensory relay neurons. Thus Lbx1 expression distinguishes between the somatosensory or viscerosensory fate of relay neurons.

Skeletal muscle growth and regeneration rely on myogenic progenitor and satellite cells, the stem cells of postnatal muscle. Elimination of Notch signals during mouse development results in premature differentiation of myogenic progenitors and formation of very small muscle groups. Here we show that this drastic effect is rescued by mutation of the muscle differentiation factor MyoD. However, rescued myogenic progenitors do not assume a satellite cell position and contribute poorly to myofiber growth. The disrupted homing is due to a deficit in basal lamina assembly around emerging satellite cells and to their impaired adhesion to myofibers. On a molecular level, emerging satellite cells deregulate the expression of basal lamina components and adhesion molecules like integrin α7, collagen XVIIIα1, Megf10, and Mcam. We conclude that Notch signals control homing of satellite cells, stimulating them to contribute to their own microenvironment and to adhere to myofibers.