Notch signaling and the generation of cell diversity in Drosophila neuroblast lineages.

Notch is a membrane bound transcription factor and it plays fundamental roles in many cell-cell interaction events usually involving directly neighboring cells relating an extrinsic signal of a sending cell to the nucleus of the receiving cell to modulate gene expression patterns in this cell. Notch regulates cell fate specification, cell proliferation as well as cell death in the contexts of many organs and cell types. Although the mechanisms of signal transduction from the cell surface to the nucleus are relatively simple, it is not fully understood how such a straightforward pathway can result in tremendously complex outcomes at the cellular level.

The glucuronyltransferase GlcAT-P is required for stretch growth of peripheral nerves in Drosophila.

During development, the growth of the animal body is accompanied by a concomitant elongation of the peripheral nerves, which requires the elongation of integrated nerve fibers and the axons projecting therein. Although this process is of fundamental importance to almost all organisms of the animal kingdom, very little is known about the mechanisms regulating this process. Here, we describe the identification and characterization of novel mutant alleles of GlcAT-P, the Drosophila ortholog of the mammalian glucuronyltransferase b3gat1.

Asymmetric cell division and Notch signaling specify dopaminergic neurons in Drosophila.

In Drosophila, dopaminergic (DA) neurons can be found from mid embryonic stages of development till adulthood. Despite their functional involvement in learning and memory, not much is known about the developmental as well as molecular mechanisms involved in the events of DA neuronal specification, differentiation and maturation. In this report we demonstrate that most larval DA neurons are generated during embryonic development.

Orthodenticle is necessary for survival of a cluster of clonally related dopaminergic neurons in the Drosophila larval and adult brain.

Background: The dopaminergic (DA) neurons present in the central brain of the Drosophila larva are spatially arranged in stereotyped groups that define clusters of bilaterally symmetrical neurons. These clusters have been classified according to anatomical criteria (position of the cell bodies within the cortex and/or projection pattern of the axonal tracts). However, information pertaining to the developmental biology, such as lineage relationship of clustered DA neurons and differential cell subtype-specific molecular markers and mechanisms of differentiation and/or survival, is currently not available.

Fetomaternal microchimerism: Some answers and many new questions.

The transfer of fetal cells into mothers during pregnancy and their organ specific integration is a well recognized phenomenon in placental vertebrates. Recently, it has been reported that some fetal cells found in the mothers have progenitor cell-like features such as multilineage differentiation potential and as a consequence they were termed pregnancy associated progenitor cells (PAPC). The multilineage differentiation potential suggested some level of cellular plasticity, which these cells share with other stem or progenitor cells.

Pregnancy-associated progenitor cells differentiate and mature into neurons in the maternal brain.

Bidirectional cell trafficking between fetus and mother during pregnancy is a well-established phenomenon observed in placental vertebrates including humans. Although studies have shown that transmigratory fetal cells, also termed pregnancy-associated progenitor cells (PAPCs), can integrate into multiple maternal organs, the integration, long-term survival, and differentiation of PAPCs in the brain has not been extensively studied. Using a murine model of fetomaternal microchimerism, we show that PAPCs integrated and persisted in several areas of the maternal brain for up to 7 months postpartum.

Genetic interactions of eyes absent, twin of eyeless and orthodenticle regulate sine oculis expression during ocellar development in Drosophila.

The homeobox gene sine oculis (so) is required for the development of the entire visual system in Drosophila, which includes the compound eyes, the ocelli, the optic lobe of the brain and the Bolwig's organ. During ocelli development, so expression labels, together with eyes absent (eya), the emergence of the ocellar precursor cells in the third instar eye-antennal disc. Footprinting and misexpression studies have led to the proposal that the Pax6 homologue twin of eyeless (toy) directly regulates the initiation of so expression in ocellar precursor cells.

Roles of db-cAMP, IBMX and RA in aspects of neural differentiation of cord blood derived mesenchymal-like stem cells.

Mesenchymal stem cells (MSCs) have multilineage differentiation potential which includes cell lineages of the central nervous system; hence MSCs might be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Although mesenchymal stem cells have been shown to differentiate into the neural lineage, there is still little knowledge about the underlying mechanisms of differentiation particularly towards specialized neurons such as dopaminergic neurons. Here, we show that MSCs derived from human umbilical cord blood (MSC(hUCBs)) are capable of expressing tyrosine hydroxylase (TH) and Nurr1, markers typically associated with DA neurons.

Insulin expressed from endogenously active glucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetes therapy.

Advances in islet transplantation have encouraged efforts to create alternative insulin-secreting cells that overcome limitations associated with current therapies. We have recently demonstrated durable correction of murine and porcine diabetes by syngeneic and autologous implantation, respectively, of primary hepatocytes non-virally modified with a glucose-responsive promoter-regulated insulin transgene. As surgical procurement of hepatocytes may be clinically unappealing, we here describe primary bone marrow-derived mesenchymal stromal cells (BMMSC) as alternative insulin-secreting bioimplants.

On the roles of Notch, Delta, kuzbanian, and inscuteable during the development of Drosophila embryonic neuroblast lineages.

The generation of cellular diversity in the nervous system involves the mechanism of asymmetric cell division. Besides an array of molecules, including the Par protein cassette, a heterotrimeric G protein signalling complex, Inscuteable plays a major role in controlling asymmetric cell division, which ultimately leads to differential activation of the Notch signalling pathway and correct specification of the two daughter cells. In this context, Notch is required to be active in one sibling and inactive in the other.

MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the posttranscriptional level. Research on miRNAs has highlighted their importance in neural development, but the specific functions of neurally enriched miRNAs remain poorly understood. We report here the expression profile of miRNAs during neuronal differentiation in the human neuroblastoma cell line SH-SY5Y.

Neural differentiation of mesenchymal-like stem cells from cord blood is mediated by PKA.

Mesenchymal stem cells (MSC) are multipotent and give rise to distinctly differentiated cells from all three germ layers. While umbilical cord blood derived mesenchymal-like cells were previously shown to be capable of differentiating into the neural lineage both in vitro and in vivo, the underlying molecular mechanisms and signal transduction pathways remain to be elucidated. In this study, we show that mesenchymal-like cells from umbilical cord blood are capable of neural differentiation and this capability is mediated by the Protein kinase A (PKA) signal transduction pathway.

Inscuteable-independent apicobasally oriented asymmetric divisions in the Drosophila embryonic CNS.

Inscuteable is the founding member of a protein complex localised to the apical cortex of Drosophila neural progenitors that controls their asymmetric division. Aspects of asymmetric divisions of all identified apicobasally oriented neural progenitors characterised to date, in both the central and peripheral nervous systems, require inscuteable. Here we examine the generality of this requirement.

The cell cycle machinery and asymmetric cell division of neural progenitors in the Drosophila embryonic central nervous system.

Asymmetric cell divisions can be mediated by the preferential segregation of intrinsic cell fate determinants into one of two sibling daughters. In dividing Drosophila neural progenitors the apical-basal orientation of the mitotic spindle, the basal cortical localization of the cell fate determinants Numb and/or Prospero as well as the coordination of these events are mediated by several proteins which include Bazooka (Baz), Inscuteable (Insc) and Partner of Inscuteable (Pins) which localize as an apical cortical complex starting at interphase. Here I will summarize data which suggest that the formation of this apical complex involves two distinct steps: (1) during the initiation of apical complex formation in interphase neuroblasts, there appears to be a hierarchical relation amongst these components where Baz recruits Insc and Baz/Insc in turn recruit Pins to the apical cortex/stalk; (2) while in delaminated mitotic neuroblasts the maintenance of the apical cortical localization of these proteins is dependent on the presence of all three components.

A requirement for Notch in the genesis of a subset of glial cells in the Drosophila embryonic central nervous system which arise through asymmetric divisions.

In the Drosophila central nervous system (CNS) glial cells are known to be generated from glioblasts, which produce exclusively glia or neuroglioblasts that bifurcate to produce both neuronal and glial sublineages. We show that the genesis of a subset of glial cells, the subperineurial glia (SPGs), involves a new mechanism and requires Notch. We demonstrate that the SPGs share direct sibling relationships with neurones and are the products of asymmetric divisions.

cdc2 links the Drosophila cell cycle and asymmetric division machineries.

Asymmetric cell divisions can be mediated by the preferential segregation of cell-fate determinants into one of two sibling daughters. In Drosophila neural progenitors, Inscuteable, Partner of Inscuteable and Bazooka localize as an apical cortical complex at interphase, which directs the apical-basal orientation of the mitotic spindle as well as the basal/cortical localization of the cell-fate determinants Numb and/or Prospero during mitosis. Although localization of these proteins shows dependence on the cell cycle, the involvement of cell-cycle components in asymmetric divisions has not been demonstrated.

Differential effects of EGF receptor signalling on neuroblast lineages along the dorsoventral axis of the Drosophila CNS.

The Drosophila ventral nerve cord derives from a stereotype population of about 30 neural stem cells, the neuroblasts, per hemineuromere. Previous experiments provided indications for inductive signals at ventral sites of the neuroectoderm that confer neuroblast identities. Using cell lineage analysis, molecular markers and cell transplantation, we show here that EGF receptor signalling plays an instructive role in CNS patterning and exerts differential effects on dorsoventral subpopulations of neuroblasts.

Binary sibling neuronal cell fate decisions in the Drosophila embryonic central nervous system are nonstochastic and require inscuteable-mediated asymmetry of ganglion mother cells.

Asymmetric cell division is a widespread mechanism in developing tissues that leads to the generation of cell diversity. In the embryonic central nervous system of Drosophila melanogaster, secondary precursor cells-ganglion mother cells (GMCs)-divide and produce postmitotic neurons that take on different cell fates. In this study, we show that binary fate decision of two pairs of sibling neurons is accomplished through the interplay of Notch (N) signaling and the intrinsic fate determinant Numb.

The embryonic central nervous system lineages of Drosophila melanogaster. I. Neuroblast lineages derived from the ventral half of the neuroectoderm.

Central nervous system development in Drosophila starts with the delamination from the neuroectoderm of about 30 neuroblasts (NBs) per hemisegment. Understanding the mechanisms leading to the specification of the individual NBs and their progeny requires the identification of their lineages. Here we describe 17 embryonic NB lineages derived from the ventral half of the neuroectoderm and we assign these lineages to identified medial and intermediate NBs.

Commitment of CNS progenitors along the dorsoventral axis of Drosophila neuroectoderm.

In the Drosophila embryo, the central nervous system (CNS) develops from a population of neural stem cells (neuroblasts) and midline progenitor cells. Here, the fate and extent of determination of CNS progenitors along the dorsoventral axis was assayed. Dorsal neuroectodermal cells transplanted into the ventral neuroectoderm or into the midline produced CNS lineages consistent with their new position.

A common precursor for glia and neurons in the embryonic CNS of Drosophila gives rise to segment-specific lineage variants.

The nervous system consists of two classes of cells, neurons and glia, which differ in morphology and function. They derive from precursors located in the neurogenic region of the ectoderm. In this study, we present the complete embryonic lineage of a neuroectodermal precursor in Drosophila that gives rise to neurons as well as glia in the abdominal CNS.