Maintaining Youth in Drosophila Neural Progenitors

An important question is how dividing stem cells maintain competence to generate multiple cell types, whereas most other cells become progressively restricted during development. The molecular basis for progenitor competence – or how competence is progressively restricted – has remained mysterious. Recent work has shown that Drosophila neuroblasts and mammalian neural progenitors are more similar than previously appreciated, and provide an excellent model system for using Drosophila genetics to unravel the molecular nature of progenitor competence and how it becomes progressively restricted during development     

Keeping neural progenitor cells on a short leash during Drosophila neurogenesis

The developmental potential of stem cells and progenitor cells must be functionally distinguished to ensure the generation of diverse cell types while maintaining the stem cell pool throughout the lifetime of an organism. In contrast to stem cells, progenitor cells possess restricted developmental potential, allowing them to give rise to only a limited number of post-mitotic progeny. Failure to establish or maintain restricted progenitor cell potential can perturb tissue development and homeostasis, and probably contributes to tumor initiation. Recent studies using the developing fruit fly Drosophila larval brain have provided molecular insight into how the developmental potential is restricted in neural progenitor cells.     

Temporal and epigenetic regulation of neurodevelopmental plasticity

The anticipated therapeutic uses of neural stem cells depend on their ability to retain a certain level of developmental plasticity. In particular, cells must respond to developmental manipulations designed to specify precise neural fates. Studies in vivo and in vitro have shown that the developmental potential of neural progenitor cells changes and becomes progressively restricted with time. For in vitro cultured neural progenitors, it is those derived from embryonic stem cells that exhibit the greatest developmental potential. It is clear that both extrinsic and intrinsic mechanisms determine the developmental potential of neural progenitors and that epigenetic, or chromatin structural, changes regulate and coordinate hierarchical changes in fate-determining gene expression. Here, we review the temporal changes in developmental plasticity of neural progenitor cells and discuss the epigenetic mechanisms that underpin these changes. We propose that understanding the processes of epigenetic programming within the neural lineage is likely to lead to the development of more rationale strategies for cell reprogramming that may be used to expand the developmental potential of otherwise restricted progenitor populations.     

Specification of neuronal identity in the embryonic CNS

One of the earliest and most crucial steps in the development of connectivity within the CNS is the acquisition of specific identities by developing neural cells. In this review, we discuss how a neural cell may come to acquire its unique identity and some of the genes that may be involved in this process. Experimental evidence suggests that ectodermal cells may pass through several phases at which their potential fates become progressively more restricted. An initial step occurs during neural induction when ectodermal cells become restricted to either a neural or non-neural fate. A little later in development, a further set of interactions determine which of the neural cells become postmitotic and begin a programme of differentiation. The differentiation phase may itself involve several steps at which the postmitotic neuron progressively advances towards its final identity.     

When timing is everything: role of cell cycle regulation in asymmetric division

Asymmetric division is a fundamental mechanism of generating cell diversity during development. One of its hallmarks is asymmetric localization during mitosis of proteins that specify daughter cell fate. Studies in Drosophila show that subcellular localization of many proteins required for asymmetric division of neuronal progenitors correlates with progression through mitosis. Yet, how cell cycle and asymmetric division machineries cooperate remains unclear. Recent data show that (1) key cell cycle regulators are required for asymmetric localization of cell fate determinants and for cell fate determination and (2) molecules that mediate asymmetric division can also act to modulate proliferation potential of progenitor cells.     

Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis

Numb and Numblike, conserved homologs of Drosophila Numb, have been implicated in cortical neurogenesis; however, analysis of their involvement in later stages of cortical development has been hampered by early lethality of double mutants in previous studies. Using Emx1(IREScre) to induce more restricted inactivation of Numb in the dorsal forebrain of numblike null mice beginning at E9.5, we have generated viable double mutants that displayed striking brain defects. It was thus possible to examine neurogenesis during the later peak phase (E12.5-E16.5). Loss of Numb and Numblike in dorsal forebrain resulted in neural progenitor hyperproliferation, delayed cell cycle exit, impaired neuronal differentiation, and concomitant defects in cortical morphogenesis. These findings reveal novel and essential function of Numb and Numblike during the peak period of cortical neurogenesis. Further, these double mutant mice provide an unprecedented viable animal model for severe brain malformations due to defects in neural progenitor cells.     

Asymmetric cell division

Asymmetric cell division is a conserved mechanism for partitioning information during mitosis. Over the past several years, significant progress has been made in our understanding of how cells establish polarity during asymmetric cell division and how determinants, in the form of localized proteins and mRNAs, are segregated. In particular, genetic studies in Drosophila and Caenorhabditis elegans have linked cell polarity, G protein signaling and regulation of the cytoskeleton to coordination of mitotic spindle orientation and localization of determinants. Also, several new studies have furthered our understanding of how asymmetrically localized cell fate determinants, such as the Numb, a negative regulator Notch signaling, functions in biasing cell fates in the developing nervous system in Drosophila. In vertebrates, analysis of dividing neural progenitor cells by in vivo imaging has raised questions about the role of asymmetric cell divisions during neurogenesis.     

Control of proliferation in the retina: temporal changes in responsiveness to FGF and TGF alpha.

Proliferation in the rat retina, as in other parts of the nervous system, occurs during a restricted period of development. In addition to regulating cell number, the mechanisms that control proliferation influence the patterning of tissues, and may affect the determination of cell type. To begin to determine how proliferation is controlled, several growth factors found in the retina were tested for effects on progenitor cell division in culture. Proliferation was enhanced by TGF alpha, bFGF and aFGF, and many of the dividing cells later differentiated into cells with the antigenic phenotypes of retinal neurons and glial cells. The mitotic response of retinal cells to these factors changed during development: progenitor cells from younger retinas (embryonic day 15 to 18; E15-E18) were more responsive to FGF's, while progenitor cells from older retinas (greater than E20) were more responsive to TGF alpha. Progenitor cells stopped dividing in vitro, even when treated with excess mitogen. These observations suggest that proliferation in the retina may be stimulated by multiple mitogenic signals provided by TGF alpha, FGF, or related factors, and that proliferation is not controlled by limiting concentrations of mitogen alone. Rather, these data demonstrate that retinal cells change during development in their responsiveness to mitogenic signals. Such changes may contribute to the regulation of proliferation.     

Cortical neuron specification: it has its time and place

Cortical neurogenesis is a highly stereotyped process in which progenitor cells generate neurons destined for specific cortical layers depending on the timing of cell cycle exit. Previous work has shown that during corticogenesis, progenitors become progressively restricted in their developmental potential. Recent work has uncovered some of the intrinsic mechanisms that underlie this fate restriction. In addition to timing, new studies suggest that the location of cell cycle exit in the cortical germinal zone may also contribute to cortical neuron specification.     

NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system

During mouse pancreas development, the transient expression of Neurogenin3 (Neurog3) in uncommitted pancreas progenitors is required to determine endocrine destiny. However it has been reported that Neurog3-expressing cells can eventually adopt acinar or ductal fates and that Neurog3 levels were important to secure the islet destiny. It is not known whether the competence of Neurog3-induced cells to give rise to non-endocrine lineages is an intrinsic property of these progenitors or depends on pancreas developmental stage. Using temporal genetic labeling approaches we examined the dynamic of endocrine progenitor differentiation and explored the plasticity of Neurog3-induced cells throughout development. We found that Neurog3(+) progenitors develop into hormone-expressing cells in a fast process taking less then 10h. Furthermore, fate-mapping studies in heterozygote (Neurog3(CreERT/+)) and Neurog3-deficient (Neurog3(CreERT/CreERT)) embryos revealed that Neurog3-induced cells have different potential over time. At the early bud stage, failed endocrine progenitors can adopt acinar or ductal fate, whereas later in the branching pancreas they do not contribute to the acinar lineage but Neurog3-deficient cells eventually differentiate into duct cells. Thus these results provide evidence that the plasticity of Neurog3-induced cells becomes restricted during development. Furthermore these data suggest that during the secondary transition, endocrine progenitor cells arise from bipotent precursors already committed to the duct/endocrine lineages and not from domain of cells having distinct potentialities.     

A cell surface differentiation antigen of Drosophila

A monoclonal antibody, generated by immunization with gastrula stage Drosophila melanogaster embryonic cells, recognizes a cell surface antigen which shows tissue and stage specificity. The antigen appears for the first time during cellularization of the blastoderm embryo and is present on all cells until around 12 hr of development. It becomes progressively restricted to specific tissues during the second half of embryogenesis. By the time of hatching, only the nervous system, germ cells, and imaginal cells are positive. During metamorphosis differentiating imaginal tissues become negative so that in the adult only the nervous system and undifferentiated germ cells are positive, with gonadal sheaths showing some staining. A third wave of antigen loss occurs during gametogenesis, resulting in negative staining on the mature sperm and oocyte. All positive tissues appear to contain the same 63-kDa cell surface antigen. The antigen behaves as a general differentiation marker lost by tissues as they approach their terminal differentiated state. The nervous system and possibly gonadal sheaths may be exceptions to this general behavior.     

Segregation of postembryonic neuronal and glial lineages inferred from a mosaic analysis of the Drosophila larval brain

Due to its intermediate complexity and its sophisticated genetic tools, the larval brain of Drosophila is a useful experimental system to study the mechanisms that control the generation of cell diversity in the CNS. In order to gain insight into the neuronal and glial lineage specificity of neural progenitor cells during postembryonic brain development, we have carried an extensive mosaic analysis throughout larval brain development. In contrast to embryonic CNS development, we have found that most postembryonic neurons and glial cells of the optic lobe and central brain originate from segregated progenitors. Our analysis also provides relevant information about the origin and proliferation patterns of several postembryonic lineages such as the superficial glia and the medial-anterior Medulla neuropile glia. Additionally, we have studied the spatio-temporal relationship between gcm expression and gliogenesis. We found that gcm expression is restricted to the post-mitotic cells of a few neuronal and glial lineages and it is mostly absent from postembryonic progenitors. Thus, in contrast to its major gliogenic role in the embryo, the function of gcm during postembryonic brain development seems to have evolved to the specification and differentiation of certain neuronal and glial lineages.     

Lineage tracing reveals the origin of Nestin-positive cells are heterogeneous and rarely from ependymal cells after spinal cord injury

Science China Life Sciences - Nestin is expressed extensively in neural stem/progenitor cells during neural development, but its expression is mainly restricted to the ependymal cells in the adult...