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1.  The proteoglycan Trol controls proliferation and differentiation of blood progenitors in the Drosophila lymph gland 
Developmental biology  2013;384(2):301-312.
The heparin sulfate proteoglycan Trol (Terribly Reduced Optic Lobes) is the D. melanogaster homolog of the vertebrate protein Perlecan. Trol is expressed as part of the extracellular matrix (ECM) found in the hematopoietic organ, called the lymph gland. In the normal lymph gland, the ECM forms thin basement membranes around individual or small groups of blood progenitors. The pattern of basement membranes, reported by Trol expression, is spatio-temporally correlated to hematopoiesis. The central, medullary zone which contain undifferentiated hematopoietic progenitors has many, closely spaced membranes. Fewer basement membranes are present in the outer, cortical zone, where differentiation of blood cells takes place. Loss of trol causes a dramatic change of the ECM into a three-dimensional, spongy mass that fills wide spaces scattered throughout the lymph gland. At the same time proliferation is reduced, leading to a significantly smaller lymph gland. Interestingly, differentiation of blood progenitors in trol mutants is precocious, resulting in the break-down of the usual zonation of the lymph gland which normally consists of an immature center (medullary zone) where cells remain undifferentiated, and an outer cortical zone, where differentiation sets in. We present evidence that the effect of Trol on blood cell differentiation is mediated by Hedgehog (Hh) signaling, which is known to be required to maintain an immature medullary zone. Overexpression of hh in the background of a trol mutation is able to rescue the premature differentiation phenotype. Our data provide novel insight into the role of the ECM component Perlecan during Drosophila hematopoiesis.
PMCID: PMC4278754  PMID: 23510717
Drosophila; hematopoiesis; lymph gland; extracellular matrix; hedgehog; Perlecan
2.  Hematopoiesis at the Onset of Metamorphosis: Terminal Differentiation and Dissociation of the Drosophila Lymph Gland 
Development genes and evolution  2011;221(3):121-131.
The D. melanogaster hematopoietic organ, called lymph gland, proliferates and differentiates throughout the larval period. The lymph gland of the late larva is comprised of a large primary lobe and several smaller secondary lobes. Differentiation into two types of hemocytes, plasmatocytes and crystal cells, is confined to the outer layer (cortical zone) of the primary lobe; the center of the primary lobe (medullary zone), as well as the secondary lobes, contain only proliferating prohemocytes. A small cluster of prohemocytes located at the posterior tip of the primary lobe serves as a signaling center (PSC) that inhibits precocious differentiation of the medullary zone. The larval lymph gland is stabilized by layers of extracellular matrix (basement membranes) that surround individual hemocytes, groups of hemocytes, as well as the lymph gland as a whole. In this paper we investigated the events shaping the lymph gland in the early pupa. The lymph gland dissociates and hemocytes disperse during the first 12h after puparium formation (APF), leaving behind empty husks of basement membrane. Prior to lymph gland dissociation, cells of the medullary zone differentiate, expressing the early differentiation marker Peroxidasin, as well as, in part, the late differentiation marker P1. Cells of the PSC spread out throughout the pupal lymph gland prior to their dispersal. Cells of the secondary lobes undergo a rapid phase of proliferation that lasts until 8h APF, followed by expression of Peroxidasin, and dispersal. These hemocytes do not express P1, indicating that they disperse prior to full maturation.
PMCID: PMC4278756  PMID: 21509534
Drosophila; blood; lymph gland; metamorphosis
3.  Postembryonic lineages of the Drosophila brain: I. Development of the lineage-associated fiber tracts 
Developmental biology  2013;384(2):10.1016/j.ydbio.2013.07.008.
Neurons of the Drosophila central brain fall into approximately 100 paired groups, termed lineages. Each lineage is derived from a single asymmetrically-dividing neuroblast. Embryonic neuroblasts produce 1,500 primary neurons (per hemisphere) that make up the larval CNS followed by a second mitotic period in the larva that generates approximately 10,000 secondary, adult-specific neurons. Clonal analyses based on previous works using lineage-specific Gal4 drivers have established that such lineages form highly invariant morphological units. All neurons of a lineage project as one or a few axon tracts (secondary axon tracts, SATs) with characteristic trajectories, thereby representing unique hallmarks. In the neuropil, SATs assemble into larger fiber bundles (fascicles) which interconnect different neuropil compartments. We have analyzed the SATs and fascicles formed by lineages during larval, pupal, and adult stages using antibodies against membrane molecules (Neurotactin/Neuroglian) and synaptic proteins (Bruchpilot/N-Cadherin). The use of these markers allows one to identify fiber bundles of the adult brain and associate them with SATs and fascicles of the larval brain. This work lays the foundation for assigning the lineage identity of GFP-labeled MARCM clones on the basis of their close association with specific SATs and neuropil fascicles, as described in the accompanying paper (Wong et al., 2013. Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones. Submitted.).
PMCID: PMC3886848  PMID: 23880429
Brain; Lineage; Circuitry; Drosophila; Mapping; Metamorphosis
4.  Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones 
Developmental biology  2013;384(2):258-289.
The Drosophila central brain is largely composed of lineages, units of sibling neurons derived from a single progenitor cell or neuroblast. During the early embryonic period neuroblast generate the primary neurons that constitute the larval brain. Neuroblasts reactivate in the larva, adding to their lineages a large number of secondary neurons which, according to previous studies in which selected lineages were labeled by stably expressed markers, differentiate during metamorphosis, sending terminal axonal and dendritic branches into defined volumes of the brain neuropil. We call the overall projection pattern of neurons forming a given lineage the “projection envelope” of that lineage. By inducing MARCM clones at the early larval stage, we labeled the secondary progeny of each neuroblast. For the supraesophageal ganglion excluding mushroom body (the part of the brain investigated in the present work) we obtained 81 different types of clones, Based on the trajectory of their secondary axon tracts (described in the accompanying paper), we assigned these clones to specific lineages defined in the larva. Since a labeled clone reveals all aspects (cell bodies, axon tracts, terminal arborization) of a lineage, we were able to describe projection envelopes for all secondary lineages of the supraesophageal ganglion. This work provides a framework by which the secondary neurons (forming the vast majority of adult brain neurons) can be assigned to genetically and developmentally defined groups. It also represents a step towards the goal to establish, for each lineage, the link between its mature anatomical and functional phenotype, and the genetic make-up of the neuroblast it descends from.
PMCID: PMC3928077  PMID: 23872236
Brain; Development; Drosophila; Lineage; Mapping; SAT
5.  From the worm’s mouth: the gene eud-1 regulates teeth and diet in nematodes 
Cell  2013;155(4):742-743.
Developmental plasticity, defined as a frequent phenomenon whereby special environmental conditions trigger different programs of development within a single species (polyphenism), plays an important role in evolutionary theory. Investigating developmental plasticity in the nematode taxon Pristionchus, Ragsdale et al. (2013) demonstrate that the activity of a single gene, eud-1, constitutes the developmental switch deciding between two different types of feeding apparatus in these animals.
PMCID: PMC4045611  PMID: 24209614
6.  The chimerical and multifaceted marine acoel Symsagittifera roscoffensis: from photosymbiosis to brain regeneration 
A remarkable example of biological engineering is the capability of some marine animals to take advantage of photosynthesis by hosting symbiotic algae. This capacity, referred to as photosymbiosis, is based on structural and functional complexes that involve two distantly unrelated organisms. These stable photosymbiotic associations between metazoans and photosynthetic protists play fundamental roles in marine ecology as exemplified by reef communities and their vulnerability to global changes threats. Here we introduce a photosymbiotic tidal acoel flatworm, Symsagittifera roscoffensis, and its obligatory green algal photosymbiont, Tetraselmis convolutae (Lack of the algal partner invariably results in acoel lethality emphasizing the mandatory nature of the photosymbiotic algae for the animal's survival). Together they form a composite photosymbiotic unit, which can be reared in controlled conditions that provide easy access to key life-cycle events ranging from early embryogenesis through the induction of photosymbiosis in aposymbiotic juveniles to the emergence of a functional “solar-powered” mature stage. Since it is possible to grow both algae and host under precisely controlled culture conditions, it is now possible to design a range of new experimental protocols that address the mechanisms and evolution of photosymbiosis. S. roscoffensis thus represents an emerging model system with experimental advantages that complement those of other photosymbiotic species, in particular corals. The basal taxonomic position of S. roscoffensis (and acoels in general) also makes it a relevant model for evolutionary studies of development, stem cell biology and regeneration. Finally, it's autotrophic lifestyle and lack of calcification make S. roscoffensis a favorable system to study the role of symbiosis in the response of marine organisms to climate change (e.g., ocean warming and acidification). In this article we summarize the state of knowledge of the biology of S. roscoffensis and its algal partner from studies dating back over a century, and provide an overview of ongoing research efforts that take advantage of this unique system.
PMCID: PMC4183113  PMID: 25324833
acoel; roscoffensis; symbiosis; regeneration; brain; algae; tetraselmis; model
7.  Initial neurogenesis in Drosophila 
Early neurogenesis comprises the phase of nervous system development during which neural progenitor cells are born. In early development, the embryonic ectoderm is subdivided by a conserved signaling mechanism into two main domains, the epidermal ectoderm and the neurectoderm. Subsequently, cells of the neurectoderm are internalized and form a cell layer of proliferating neural progenitors. In vertebrates, the entire neurectoderm folds into the embryo to give rise to the neural tube. In Drosophila and many other invertebrates, a subset of neurectodermal cells, called neuroblasts (NBs), delaminates and forms the neural primordium inside the embryo where they divide in an asymmetric, stem cell-like mode. The remainder of the neuroectodermal cells that stay behind at the surface loose their neurogenic potential and later give rise to the ventral part of the epidermis. The genetic and molecular analysis of the mechanisms controlling specification and proliferation of NBs in the Drosophila embryo, which played a significant part in pioneering the field of modern developmental neurobiology, represents the topic of this review.
PMCID: PMC3928071  PMID: 24014455
8.  Neuroblast lineage-specific origin of the neurons of the Drosophila larval olfactory system 
Developmental biology  2012;373(2):322-337.
The complete neuronal repertoire of the central brain of Drosophila originates from only approximately 100 pairs of neural stem cells, or neuroblasts. Each neuroblast produces a highly stereotyped lineage of neurons which innervate specific compartments of the brain. Neuroblasts undergo two rounds of mitotic activity: embryonic divisions produce lineages of primary neurons that build the larval nervous system; after a brief quiescence, the neuroblasts go through a second round of divisions in larval stage to produce secondary neurons which are integrated into the adult nervous system. Here we investigate the lineages that are associated with the larval antennal lobe, one of the most widely studied neuronal systems in fly. We find that the same five neuroblasts responsible for the adult antennal lobe also produce the antennal lobe of the larval brain. However, there are notable differences in the composition of larval (primary) lineages and their adult (secondary) counterparts. Significantly, in the adult, two lineages (lNB/BAlc and adNB/BAmv3) produce uniglomerular projection neurons connecting the antennal lobe with the mushroom body and lateral horn; another lineage, vNB/BAla1, generates multiglomerular neurons reaching the lateral horn directly. lNB/BAlc, as well as a fourth lineage, vlNB/BAla2, generate a diversity of local interneurons. We describe a fifth, previously unknown lineage, BAlp4, which connects the posterior part of the antennal lobe and the neighboring tritocerebrum (gustatory center) with a higher brain center located adjacent to the mushroom body. In the larva, only one of these lineages, adNB/BAmv3, generates all uniglomerular projection neurons. Also as in the adult, lNB/BAlc and vlNB/BAla2 produce local interneurons which, in terms of diversity in architecture and transmitter expression, resemble their adult counterparts. In addition, lineages lNB/BAlc and vNB/BAla1, as well as the newly described BAlp4, form numerous types of projection neurons which along the same major axon pathways (antennal tracts) used by the antennal projection neurons, but which form connections that include regions outside the “classical” olfactory circuit triad antennal lobe-mushroom body-lateral horn. Our work will benefit functional studies of the larval olfactory circuit, and shed light on the relationship between larval and adult neurons.
PMCID: PMC4045504  PMID: 23149077
Drosophila; Larval olfactory system; Local interneuron; Projection neuron; Olfactory lineage
Development genes and evolution  2012;223(3):10.1007/s00427-012-0423-7.
Flatworms are classically considered to represent the simplest organizational form of all living bilaterians with a true central nervous system. Based on their simple body plans, all flatworms have been traditionally grouped together in a single phylum at the base of the bilaterians. Current molecular phylogenomic studies now split the flatworms into two widely separated clades, the acoelomorph flatworms and the platyhelminth flatworms, such that the last common ancestor of both clades corresponds to the urbilaterian ancestor of all bilaterian animals. Remarkably, recent comparative neuroanatomical analyses of acoelomorphs and platyhelminths show that both of these flatworm groups have complex anterior brains with surprisingly similar basic neuroarchitectures. Taken together, these findings imply that fundamental neuroanatomical features of the brain in the two separate flatworm groups are likely to be primitive and derived from the urbilaterian brain.
PMCID: PMC3873165  PMID: 23143292
brain; evolution; acoel; platyhelminth; urbilateria
10.  Genetic control of intestinal stem cell specification and development: a comparative view 
Stem cell reviews  2012;8(2):597-608.
Stem cells of the adult vertebrate intestine (ISCs) are responsible for the continuous replacement of intestinal cells, but also serve as site of origin of intestinal neoplasms. The interaction between multiple signaling pathways, including Wnt/Wg, Shh/Hh, BMP, and Notch, orchestrate mitosis, motility, and differentiation of ISCs. Many fundamental questions of how these pathways carry out their function remain unanswered. One approach to gain more insight is to look at the development of stem cells, to analyze the “programming” process which these cells undergo as they emerge from the large populations of embryonic progenitors. This review intends to summarize pertinent data on vertebrate intestinal stem cell biology, to then take a closer look at recent studies of intestinal stem cell development in Drosophila. Here, stem cell pools and their niche environment consist of relatively small numbers of cells, and questions concerning the pattern of cell division, niche-stem cell contacts, or differentiation can be addressed at the single cell level. Likewise, it is possible to analyze the emergence of stem cells during development more easily than in vertebrate systems: where in the embryo do stem cells arise, what structures in their environment do they interact with, and what signaling pathways are active sequentially as a result of these interactions. Given the high degree of conservation among genetic mechanisms controlling stem cell behavior in all animals, findings in Drosophila will provide answers that inform research in the vertebrate stem cell field.
PMCID: PMC3950647  PMID: 22529012
11.  A novel tissue in an established model system: the Drosophila pupal midgut 
Development genes and evolution  2011;221(2):69-81.
The Drosophila larval and adult midgut are derived from two populations of endodermal progenitors that separate from each other in the early embryo. As larval midgut cells differentiate into an epithelial layer, adult midgut progenitors (AMPs) remain as small clusters of proliferating, undifferentiated cells attached to the basal surface of the larval gut epithelium. During the first few hours of metamorphosis, AMPs merge into a continuous epithelial tube that overgrows the larval layer and differentiates into the adult midgut; at the same time, the larval midgut degenerates. As shown in this paper, there is a second, transient pupal midgut that develops from the AMPs at the beginning of metamorphosis, and that intercalates between the adult and larval midgut epithelia. Cells of the transient pupal midgut form a multilayered tube that exhibits signs of differentiation, in the form of septate junctions and rudimentary apical microvilli. Some cells of the pupal midgut develop as endocrine cells. The pupal midgut remains closely attached to the degenerating larval midgut cells. Along with these cells, pupal midgut cells are sequestered into the lumen where they form the compact “yellow body”. The formation of a pupal midgut has been reported from several other species, and may represent a general feature of intestinal metamorphosis in insects.
PMCID: PMC3950650  PMID: 21556856
Drosophila; midgut; metamorphosis; pupa; ultrastructure
12.  Drosophila brain development: Closing the gap between a macroarchitectural and microarchitectural approach 
Neurobiologists address neural structure, development and function at the level of “macrocircuits” (how are different brain compartments interconnected, what overall pattern of activity do they produce), and at the level of “microcircuits” (how does connectivity and physiology of individual neurons and their processes within a compartment determine the functional output of this compartment). Work in our lab aims at reconstructing the developing Drosophila brain at both levels. Macrocircuits can be approached conveniently by reconstructing the pattern of brain lineages, which form groups of neurons whose projections form cohesive fascicles interconnecting the compartments of the larval and adult brain. The reconstruction of microcircuits requires serial section electron microscopy, due to the small size of terminal neuronal processes and their synaptic contacts. Because of the amount of labor that traditionally comes with this approach, very little is known about microcircuitry in brains across the animal kingdom. Many of the problems of serial EM reconstruction is now solvable with digital image recording and specialized software for both image acquisition and post-processing. In this paper we introduce our efforts to reconstruct the small Drosophila larval brain, and discuss our results in light of the published data on neuropile ultrastructure in other animal taxa.
PMCID: PMC3950651  PMID: 20028843
Drosophila; brain; lineage; connectivity; elctron microscopy
13.  Structure and Development of Glia in Drosophila 
Glia  2011;59(9):1237-1252.
Insect glia represents a conspicuous and diverse population of cells and plays a role in controlling neuronal progenitor proliferation, axonal growth, neuronal differentiation and maintenance, and neuronal function. Genetic studies in Drosophila have elucidated many aspects of glial structure, function and development. Just as in vertebrates, it appears as if different classes of glial cells are specialized for different functions. Based on topology and cell shape, glial cells of the central nervous system fall into three classes (Fig. 1A–C): (i) surface glia that extend sheath-like processes to wrap around the entire brain; (ii) cortex glia (also called cell body-associated glia) that encapsulate neuronal somata and neuroblasts which form the outer layer (cortex) of the central nervous system; (iii) neuropile glia that are located at the interface between the cortex and the neuropile, the central domain of the nervous system formed by the highly branched neuronal processes and their synaptic contacts. Surface glia is further subdivided into an outer, perineurial layer, and an inner, subperineurial layer. Likewise, neuropile glia comprises a class of cells that remain at the surface of the neuropile (ensheathing glia), and a second class that forms profuse lamellar processes around nerve fibers within the neuropile (astrocyte-like or reticular glia). Glia also surrounds the peripheral nerves and sensory organs; here, one also recognizes perineurial and subperineurial glia, and a third type called “wrapping glia” that most likely corresponds to the ensheathing glia of the central nervous system. Much more experimental work is needed to determine how fundamental these differences between classes of glial cells are, or how and when during development they are specified. To aid in this work the following review will briefly summarize our knowledge of the classes of glial cells encountered in the Drosophila nervous system, and then survey their development from the embryo to adult.
PMCID: PMC3950653  PMID: 21438012
14.  Conserved Genetic Pathways Controlling the Development of the Diffuse Endocrine System in Vertebrates and Drosophila 
The midgut epithelium is formed by absorptive enterocytes, secretory cells and endocrine cells. Each of these lineages is derived from the pluripotent progenitors that constitute the embryonic endoderm; the mature midgut retains pools of self-renewing stem cells that continue to produce all lineages. Recent findings in vertebrates and Drosophila shed light on the genetic mechanism that specifies the fate of the different lineages. A pivotal role is played by the Notch signaling pathway that, in a manner that appears to be very similar to the way in which Notch signaling selects neural progenitors within the neurectoderm, distinguishes the fate of secretory/endocrine cells and enterocytes. Proneural genes encoding bHLH transcription factors are expressed and required in prospective endocrine cells; activation of the Notch pathways restricts the number of these cells and promotes enterocyte development. In this review we compare the development of the intestinal endocrine cells in vertebrates and insects and summarize recent findings dealing with genetic pathways controlling this cell type.
PMCID: PMC3950663  PMID: 20005229
Drosophila; vertebrate; endocrine; gut; development; stem cell; Notch
15.  Neuronal fiber tracts connecting the brain and ventral nerve cord of the early Drosophila larva 
Using a combination of dye injections, clonal labeling, and molecular markers we have reconstructed the axonal connections between brain and ventral nerve cord of the first instar Drosophila larva. Out of the approximately 1400 neurons that form the early larval brain hemisphere, less than 50 cells have axons descending into the ventral nerve cord. Descending neurons fall into four topologically defined clusters located in the antero-medial, antero-lateral, dorsal, and baso-posterior brain, respectively. The antero-lateral cluster represents a lineage derived from a single neuroblast. Terminations of descending neurons are almost exclusively found in the anterior part of the ventral nerve cord, represented by the gnathal and thoracic neuromeres. This region also contains small numbers of neurons with axons ascending into the brain. Terminals of the ascending axons are found in the same basal brain regions that also contain descending neurons. We have mapped ascending and descending axons to the previously described scaffold of longitudinal fiber tracts that interconnect different neuromeres of the ventral nerve cord and the brain. This work provides a structural framework for functional and genetic studies addressing the control of Drosophila larval behavior by brain circuits.
PMCID: PMC3950755  PMID: 19459219
Drosophila; brain; ventral nerve cord; connectivity; ascending axons; descending axons
16.  Hematopoiesis and Hematopoietic Organs in Arthropods 
Development genes and evolution  2013;223(0):10.1007/s00427-012-0428-2.
Hemocytes (blood cells) are motile cells moving throughout the extracellular space and exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.
PMCID: PMC3873168  PMID: 23319182
blood; hematopoiesis; stem cell; invertebrate; arthropod
17.  Stem cells and lineages of the intestine: a developmental and evolutionary perspective 
Development genes and evolution  2012;223(0):10.1007/s00427-012-0422-8.
The intestine consists of epithelial cells that secrete digestive enzymes and mucus (gland cells), absorb food particles (enterocytes), and produce hormones (endocrine cells). Intestinal cells are rapidly turned over and need to be replaced. In cnidarians, mitosis of differentiated intestinal cells accounts for much of the replacement; in addition, migratory, multipotent stem cells (interstitial cells) contribute to the production of intestinal cells. In other phyla, intestinal cell replacement is solely the function of stem cells entering the gut from the outside (such as in case of the neoblasts of platyhelmints) or intestinal stem cells located within the midgut epithelium (as in both vertebrates or arthropods). We will attempt in the following to review important aspects of midgut stem cells in different animal groups: where are they located, what types of lineages do they produce, and how do they develop. We will start out with a comparative survey of midgut cell types found across the animal kingdom; then briefly look at the specification of these cells during embryonic development; and finally focus on the stem cells that regenerate midgut cells during adult life. In a number of model systems, including mouse, zebrafish and Drosophila, the molecular pathways controlling ISC proliferation and the specification of intestinal cell types are under intensive investigation. We will highlight findings of the recent literature, focusing on aspects that are shared between the different models and that point at evolutionary ancient mechanisms of intestinal cell formation.
PMCID: PMC3873164  PMID: 23179635
intestine; stem cell; cell fate; development; evolution
18.  Stem cells in the context of evolution and development 
Development genes and evolution  2012;223(0):10.1007/s00427-012-0430-8.
PMCID: PMC3882194  PMID: 23223955
19.  Gene expression patterns in primary neuronal clusters of the Drosophila embryonic brain 
Gene expression patterns : GEP  2007;7(5):584-595.
The brain of Drosophila is formed by approximately 100 lineages, each lineage being derived from a stem cell-like neuroblast that segregates from the procephalic neurectoderm of the early embryo. A neuroblast map has been established in great detail for the early embryo, and a suite of molecular markers has been defined for all neuroblasts included in this map (Urbach and Technau, 2003a). However, the expression of these markers was not followed into later embryonic or larval stages, mainly due to the fact that anatomical landmarks to which expression patterns could be related had not been defined. Such markers, in the form of stereotyped clusters of neurons whose axons project along cohesive bundles (“primary axon bundles” or “PABs”) are now available (Younossi-Hartenstein et al., 2006). In the present study we have mapped the expression of molecular markers in relationship to primary neuronal clusters and their PABs. The markers we analyzed include many of the genes involved in patterning of the brain along the anteroposterior axis (cephalic gap genes, segment polarity genes) and dorso-ventral axis (columnar patterning genes), as well as genes expressed in the dorsal protocerebrum and visual system (early eye genes). Our analysis represents an important step along the way to identify neuronal lineages of the mature brain with genes expressed in the early embryo in discrete neuroblasts. Furthermore, the analysis helped us to reconstruct the morphogenetic movements that transform the two-dimensional neuroblast layer of the early embryo into the three-dimensional larval brain and provides the basis for deeper understanding of how the embryonic brain develops.
PMCID: PMC3928073  PMID: 17300994
Drosophila; embryonic brain; brain development; Hox genes; pair rule genes; segment polarity genes; head gap genes; retinal patterning genes; columnar patterning genes
20.  A map of brain neuropils and fiber systems in the ant Cardiocondyla obscurior 
A wide spectrum of occupied ecological niches and spectacular morphological adaptations make social insects a prime object for comparative neuroanatomical studies. Eusocial insects have evolved complex societies based on caste polyphenism. A diverse behavioral repertoire of morphologically distinct castes of the same species requires a high degree of plasticity in the central nervous system. We have analyzed the central brain neuropils and fiber tract systems of the worker of the ant Cardiocondyla obscurior, a model for the study of social traits. Our analysis is based on whole mount preparations of adult brains labeled with an antibody against Drosophila-Synapsin, which cross-reacts strongly with synapses in Cardiocondyla. Neuropil compartments stand out as domains with a certain texture and intensity of the anti-Synapsin signal. By contrast, fiber tracts, which are composed of bundles of axons accompanied by glia and are devoid of synapses, appear as channels or sheaths with low anti-Synapsin signal. We have generated a digital 3D atlas of the Cardiocondyla brain neuropil. The atlas provides a reference for future studies of brain polymorphisms in distinct castes, brain development or localization of neurotransmitter systems.
PMCID: PMC4316776
neuropile compartements; Cardiocondyla obscurior; neuroanatomy; fiber tracts; hymenoptera
21.  Development of the Drosophila entero-endocrine lineage and its specification by the Notch signaling pathway 
Developmental biology  2011;353(2):10.1016/j.ydbio.2011.01.039.
In this paper we have investigated the developmental-genetic steps that shape the entero-endocrine system of Drosophila melanogaster from the embryo to the adult. The process starts in the endoderm of the early embryo where precursors of endocrine cells and enterocytes of the larval midgut, as well as progenitors of the adult midgut, are specified by a Notch signaling-dependent mechanism. In a second step that occurs during the late larval period, enterocytes and endocrine cells of a transient pupal midgut are selected from within the clusters of adult midgut progenitors. As in the embryo, activation of the Notch pathway triggers enterocyte differentiation, and inhibits cells from further proliferation or choosing the endocrine fate. The third step of entero-endocrine cell development takes place at a mid-pupal stage. Before this time point, the epithelial layer destined to become the adult midgut is devoid of endocrine cells. However, precursors of the intestinal midgut stem cells (pISCs) are already present. After an initial phase of symmetric divisions which causes an increase in their own population size, pISCs start to spin off cells that become postmitotic and express the endocrine fate marker, Prospero. Activation of Notch in pISCs forces these cells into an enterocyte fate. Loss of Notch function causes an increase in the proliferatory activity of pISCs, as well as a higher ratio of Prospero-positive cells.
PMCID: PMC3873147  PMID: 21382366
entero-endocrine cell; midgut; stem cell; Drosophila; Notch
22.  The Drosophila larval visual system: high-resolution analysis of a simple visual neuropil 
Developmental biology  2011;358(1):10.1016/j.ydbio.2011.07.006.
The task of the visual system is to translate light into neuronal encoded information. This translation of photons into neuronal signals is achieved by photoreceptor neurons (PRs), specialized sensory neurons, located in the eye. Upon perception of light the PRs will send a signal to target neurons, which represent a first station of visual processing. Increasing complexity of visual processing stems from the number of distinct PR-subtypes and their various types of target neurons that are contacted. The visual system of the fruit fly larva represents a simple visual system (larval optic neuropil, LON) that consists of 12 PRs falling into two classes: blue-senstive PRs expressing Rhodopsin 5 (Rh5) and green-sensitive PRs expressing Rhodopsin 6 (Rh6). These afferents contact a small number of target neurons, including optic lobe pioneers (OLPs) and lateral clock neurons (LNs). We combine the use of genetic markers to label both PR-subtypes and the distinct, identifiable sets of target neurons with a serial EM reconstruction to generate a high-resolution map of the larval optic neuropil. We find that the larval optic neuropil shows a clear bipartite organization consisting of one domain innervated by PRs and one devoid of PR axons. The topology of PR projections, in particular the relationship between Rh5 and Rh6 afferents, is maintained from the nerve entering the brain to the axon terminals. The target neurons can be subdivided according to neurotransmitter or neuropeptide they use as well as the location within the brain. We further track the larval optic neuropil through development from first larval instar to its location in the adult brain as the accessory medulla.
PMCID: PMC3873161  PMID: 21781960
Drosophila; larval visual system; serial EM analysis; photoreceptors; sensory systems
23.  Spatial expression of transcription factors in Drosophila embryonic organ development 
Genome Biology  2013;14(12):R140.
Site-specific transcription factors (TFs) bind DNA regulatory elements to control expression of target genes, forming the core of gene regulatory networks. Despite decades of research, most studies focus on only a small number of TFs and the roles of many remain unknown.
We present a systematic characterization of spatiotemporal gene expression patterns for all known or predicted Drosophila TFs throughout embryogenesis, the first such comprehensive study for any metazoan animal. We generated RNA expression patterns for all 708 TFs by in situ hybridization, annotated the patterns using an anatomical controlled vocabulary, and analyzed TF expression in the context of organ system development. Nearly all TFs are expressed during embryogenesis and more than half are specifically expressed in the central nervous system. Compared to other genes, TFs are enriched early in the development of most organ systems, and throughout the development of the nervous system. Of the 535 TFs with spatially restricted expression, 79% are dynamically expressed in multiple organ systems while 21% show single-organ specificity. Of those expressed in multiple organ systems, 77 TFs are restricted to a single organ system either early or late in development. Expression patterns for 354 TFs are characterized for the first time in this study.
We produced a reference TF dataset for the investigation of gene regulatory networks in embryogenesis, and gained insight into the expression dynamics of the full complement of TFs controlling the development of each organ system.
PMCID: PMC4053779  PMID: 24359758
24.  Fiji - an Open Source platform for biological image analysis 
Nature methods  2012;9(7):10.1038/nmeth.2019.
Fiji is a distribution of the popular Open Source software ImageJ focused on biological image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image processing algorithms. Fiji facilitates the transformation of novel algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
PMCID: PMC3855844  PMID: 22743772
25.  X11/Mint Genes Control Polarized Localization of Axonal Membrane Proteins in Vivo 
The Journal of Neuroscience  2013;33(19):8575-8586.
Mislocalization of axonal proteins can result in misassembly and/or miswiring of neural circuits, causing disease. To date, only a handful of genes that control polarized localization of axonal membrane proteins have been identified. Here we report that Drosophila X11/Mint proteins are required for targeting several proteins, including human amyloid precursor protein (APP) and Drosophila APP-like protein (APPL), to axonal membranes and for their exclusion from dendrites of the mushroom body in Drosophila, a brain structure involved in learning and memory. Axonal localization of APP is mediated by an endocytic motif, and loss of X11/Mint results in a dramatic increase in cell-surface levels of APPL, especially on dendrites. Mutations in genes required for endocytosis show similar mislocalization of these proteins to dendrites, and strongly enhance defects seen in X11/Mint mutants. These results suggest that X11/Mint-dependent endocytosis in dendrites may serve to promote the axonal localization of membrane proteins. Since X11/Mint binds to APP, and abnormal trafficking of APP contributes to Alzheimer's disease, deregulation of X11/Mint may be important for Alzheimer's disease pathogenesis.
PMCID: PMC3865514  PMID: 23658195

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