Ian A Meinertzhagen

University of Utah, Salt Lake City, UT, United States

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Publications (180)937.87 Total impact

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    Ying Xu · Futing An · Jolanta A Borycz · Janusz Borycz · Ian A Meinertzhagen · Tao Wang
    [Show abstract] [Hide abstract] ABSTRACT: Histamine is an important chemical messenger that regulates multiple physiological processes in both vertebrate and invertebrate animals. Even so, how glial cells and neurons recycle histamine remains to be elucidated. Drosophila photoreceptor neurons use histamine as a neurotransmitter, and the released histamine is recycled through neighboring glia, where it is conjugated to β-alanine to form carcinine. However, how carcinine is then returned to the photoreceptor remains unclear. In an mRNA-seq screen for photoreceptor cell-enriched transporters, we identified CG9317, an SLC22 transporter family protein, and named it CarT (Carcinine Transporter). S2 cells that express CarT are able to take up carcinine in vitro. In the compound eye, CarT is exclusively localized to photoreceptor terminals. Null mutations of cart alter the content of histamine and its metabolites. Moreover, null cart mutants are defective in photoreceptor synaptic transmission and lack phototaxis. These findings reveal that CarT is required for histamine recycling at histaminergic photoreceptors and provide evidence for a CarT-dependent neurotransmitter trafficking pathway between glial cells and photoreceptor terminals.
    Full-text · Article · Dec 2015 · PLoS Genetics
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    Alberto Stolfi · Kerrianne Ryan · Ian A. Meinertzhagen · Lionel Christiaen
    Preview · Dataset · Nov 2015
  • Alberto Stolfi · Kerrianne Ryan · Ian A Meinertzhagen · Lionel Christiaen
    [Show abstract] [Hide abstract] ABSTRACT: The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws. During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail and Pax3/7 and generate melanin-containing pigment cells, a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate several cell types. Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis, the bipolar tail neuron, shares a set of features with neural-crest-derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs.
    No preview · Article · Nov 2015 · Nature
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    [Show abstract] [Hide abstract] ABSTRACT: We reconstructed the synaptic circuits of seven columns in the second neuropil or medulla behind the fly's compound eye. These neurons embody some of the most stereotyped circuits in one of the most miniaturized of animal brains. The reconstructions allow us, for the first time to our knowledge, to study variations between circuits in the medulla's neighboring columns. This variation in the number of synapses and the types of their synaptic partners has previously been little addressed because methods that visualize multiple circuits have not resolved detailed connections, and existing connectomic studies, which can see such connections, have not so far examined multiple reconstructions of the same circuit. Here, we address the omission by comparing the circuits common to all seven columns to assess variation in their connection strengths and the resultant rates of several different and distinct types of connection error. Error rates reveal that, overall, <1% of contacts are not part of a consensus circuit, and we classify those contacts that supplement (E+) or are missing from it (E-). Autapses, in which the same cell is both presynaptic and postsynaptic at the same synapse, are occasionally seen; two cells in particular, Dm9 and Mi1, form ≥20-fold more autapses than do other neurons. These results delimit the accuracy of developmental events that establish and normally maintain synaptic circuits with such precision, and thereby address the operation of such circuits. They also establish a precedent for error rates that will be required in the new science of connectomics.
    Full-text · Article · Oct 2015 · Proceedings of the National Academy of Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: The promise of extracting connectomes and performing useful analysis on large electron microscopy (EM) datasets has been an elusive dream for many years. Tracing in even the smallest portions of neuropil requires copious human annotation, the rate-limiting step for generating a connectome. While a combination of improved imaging and automatic segmentation will lead to the analysis of increasingly large volumes, machines still fail to reach the quality of human tracers. Unfortunately, small errors in image segmentation can lead to catastrophic distortions of the connectome. In this paper, to analyze very large datasets, we explore different mechanisms that are less sensitive to errors in automation. Namely, we advocate and deploy extensive synapse detection on the entire antennal lobe (AL) neuropil in the brain of the fruit fly Drosophila, a region much larger than any densely annotated to date. The resulting synapse point cloud produced is invaluable for determining compartment boundaries in the AL and choosing specific regions for subsequent analysis. We introduce our methodology in this paper for region selection and show both manual and automatic synapse annotation results. Finally, we note the correspondence between image datasets obtained using the synaptic marker, antibody nc82, and our datasets enabling registration between light and EM image modalities.
    Full-text · Article · Aug 2015
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    Ruth Fabian-Fine · Shannon Meisner · Päivi H Torkkeli · Ian A Meinertzhagen
    [Show abstract] [Hide abstract] ABSTRACT: Spider sensory neurons with cell bodies close to various sensory organs are innervated by putative efferent axons from the central nervous system (CNS). Light and electronmicroscopic imaging of immunolabeled neurons has demonstrated that neurotransmitters present at peripheral synapses include γ-aminobutyric acid (GABA), glutamate and octopamine. Moreover, electrophysiological studies show that these neurotransmitters modulate the sensitivity of peripheral sensory neurons. Here, we undertook immunocytochemical investigations to characterize GABA and glutamate-immunoreactive neurons in three-dimensional reconstructions of the spider CNS. We document that both neurotransmitters are abundant in morphologically distinct neurons throughout the CNS. Labeling for the vesicular transporters, VGAT for GABA and VGLUT for glutamate, showed corresponding patterns, supporting the specificity of antibody binding. Whereas some neurons displayed strong immunolabeling, others were only weakly labeled. Double labeling showed that a subpopulation of weakly labeled neurons present in all ganglia expresses both GABA and glutamate. Double labeled, strongly and weakly labeled GABA and glutamate immunoreactive axons were also observed in the periphery along muscle fibers and peripheral sensory neurons. Electron microscopic investigations showed presynaptic profiles of various diameters with mixed vesicle populations innervating muscle tissue as well as sensory neurons. Our findings provide evidence that: (1) sensory neurons and muscle fibers are innervated by morphologically distinct, centrally located GABA- and glutamate immunoreactive neurons; (2) a subpopulation of these neurons may co-release both neurotransmitters; and (3) sensory neurons and muscles are innervated by all of these neurochemically and morphologically distinct types of neurons. The biochemical diversity of presynaptic innervation may contribute to how spiders filter natural stimuli and coordinate appropriate response patterns.
    Full-text · Article · Jul 2015 · Cell and Tissue Research
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    [Show abstract] [Hide abstract] ABSTRACT: Synaptic circuits for identified behaviors in the Drosophila brain have typically been considered from either a developmental or functional perspective without reference to how the circuits might have been inherited from ancestral forms. For example, two candidate pathways for ON- and OFF-edge motion detection in the visual system act via circuits that use respectively either T4 or T5, two cell types of the fourth neuropil, or lobula plate (LOP), that exhibit narrow-field direction-selective responses and provide input to wide-field tangential neurons. T4 or T5 both have four subtypes that terminate one each in the four strata of the LOP. Representatives are reported in a wide range of Diptera, and both cell types exhibit various similarities in: (1) the morphology of their dendritic arbors; (2) their four morphological and functional subtypes; (3) their cholinergic profile in Drosophila; (4) their input from the pathways of L3 cells in the first neuropil, or lamina (LA), and by one of a pair of LA cells, L1 (to the T4 pathway) and L2 (to the T5 pathway); and (5) their innervation by a single, wide-field contralateral tangential neuron from the central brain. Progenitors of both also express the gene atonal early in their proliferation from the inner anlage of the developing optic lobe, being alone among many other cell type progeny to do so. Yet T4 receives input in the second neuropil, or medulla (ME), and T5 in the third neuropil or lobula (LO). Here we suggest that these two cell types were originally one, that their ancestral cell population duplicated and split to innervate separate ME and LO neuropils, and that a fiber crossing-the internal chiasma-arose between the two neuropils. The split most plausibly occurred, we suggest, with the formation of the LO as a new neuropil that formed when it separated from its ancestral neuropil to leave the ME, suggesting additionally that ME input neurons to T4 and T5 may also have had a common origin.
    Full-text · Article · Jul 2015 · Frontiers in Neural Circuits
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    Tina Schwabe · Jolanta A Borycz · Ian A Meinertzhagen · Thomas R Clandinin
    [Show abstract] [Hide abstract] ABSTRACT: Background: Neuronal circuits in worms, flies, and mammals are organized so as to minimize wiring length for a functional number of synaptic connections, a phenomenon called wiring optimization. However, the molecular mechanisms that establish optimal wiring during development are unknown. We addressed this question by studying the role of N-cadherin in the development of optimally wired neurite fascicles in the peripheral visual system of Drosophila. Results: Photoreceptor axons surround the dendrites of their postsynaptic targets, called lamina cells, within a concentric fascicle called a cartridge. N-cadherin is expressed at higher levels in lamina cells than in photoreceptors, and all genetic manipulations that invert these relative differences displace lamina cells to the periphery and relocate photoreceptor axon terminals into the center. Conclusions: Differential expression of a single cadherin is both necessary and sufficient to determine cartridge structure because it positions the most-adhesive elements that make the most synapses at the core and the less-adhesive elements that make fewer synapses at the periphery. These results suggest a general model by which differential adhesion can be utilized to determine the relative positions of axons and dendrites to establish optimal wiring.
    Preview · Article · May 2014 · Current Biology
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    [Show abstract] [Hide abstract] ABSTRACT: In the fly's visual motion pathways, two cell types-T4 and T5-are the first known relay neurons to signal small-field direction-selective motion responses [1]. These cells then feed into large tangential cells that signal wide-field motion. Recent studies have identified two types of columnar neurons in the second neuropil, or medulla, that relay input to T4 from L1, the ON-channel neuron in the first neuropil, or lamina, thus providing a candidate substrate for the elementary motion detector (EMD) [2]. Interneurons relaying the OFF channel from L1's partner, L2, to T5 are so far not known, however. Here we report that multiple types of transmedulla (Tm) neurons provide unexpectedly complex inputs to T5 at their terminals in the third neuropil, or lobula. From the L2 pathway, single-column input comes from Tm1 and Tm2 and multiple-column input from Tm4 cells. Additional input to T5 comes from Tm9, the medulla target of a third lamina interneuron, L3, providing a candidate substrate for L3's combinatorial action with L2 [3]. Most numerous, Tm2 and Tm9's input synapses are spatially segregated on T5's dendritic arbor, providing candidate anatomical substrates for the two arms of a T5 EMD circuit; Tm1 and Tm2 provide a second. Transcript profiling indicates that T5 expresses both nicotinic and muscarinic cholinoceptors, qualifying T5 to receive cholinergic inputs from Tm9 and Tm2, which both express choline acetyltransferase (ChAT). We hypothesize that T5 computes small-field motion signals by integrating multiple cholinergic Tm inputs using nicotinic and muscarinic cholinoceptors.
    Full-text · Article · Apr 2014 · Current biology: CB
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    [Show abstract] [Hide abstract] ABSTRACT: Each neuropil module, or cartridge, in the fly's lamina has a fixed complement of cells. Of five types of monopolar cell interneurons, only L4 has collaterals that invade neighboring cartridges. In the proximal lamina, these collaterals form reciprocal synapses with both the L2 of their own cartridge and the L4 collateral branches from two other neighboring cartridges. During synaptogenesis, L4 collaterals strongly express the cell adhesion protein Kirre, a member of the irre cell recognition module (IRM) group of proteins ( Fischbach et al., 2009 , J Neurogenet, 23, 48-67). The authors show by mutant analysis and gene knockdown techniques that L4 neurons develop their lamina collaterals in the absence of this cell adhesion protein. Using electron microscopy (EM), the authors demonstrate, however, that without Kirre protein these L4 collaterals selectively form fewer synapses. The collaterals of L4 neurons of various genotypes reconstructed from serial-section EM revealed that the number of postsynaptic sites was dramatically reduced in the absence of Kirre, almost eliminating any synaptic input to L4 neurons. A significant reduction of presynaptic sites was also detected in kirre(0) mutants and gene knockdown flies using RNA interference. L4 neuron reciprocal synapses are thus almost eliminated. A presynaptic marker, Brp-short(GFP) confirmed these data using confocal microscopy. This study reveals that removing Kirre protein specifically disrupts the functional L4 synaptic network in the Drosophila lamina.
    Full-text · Article · Apr 2014 · Journal of neurogenetics
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    [Show abstract] [Hide abstract] ABSTRACT: The small GTPase Rab7 is a key regulator of endosomal maturation in eukaryotic cells. Mutations in rab7 are thought to cause the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B) by a gain-of-function mechanism. Here we show that loss of rab7, but not overexpression of rab7 CMT2B mutants, causes adult-onset neurodegeneration in a Drosophila model. All CMT2B mutant proteins retain 10–50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. Consequently, expression of CMT2B mutants at levels between 0.5 and 10-fold their endogenous levels fully rescues the neuropathy-like phenotypes of the rab7 mutant. Live imaging reveals that CMT2B proteins are inefficiently recruited to endosomes, but do not impair endosomal maturation. These findings are not consistent with a gain-of-function mechanism. Instead, they indicate a dosage-dependent sensitivity of neurons to rab7-dependent degradation. Our results suggest a therapeutic approach opposite to the currently proposed reduction of mutant protein function. DOI: http://dx.doi.org/10.7554/eLife.01064.001
    Full-text · Article · Dec 2013 · eLife Sciences
  • M Burrows · I A Meinertzhagen · P Bräunig
    [Show abstract] [Hide abstract] ABSTRACT: The planthopper insect Issus produces one of the fastest and most powerful jumps of any insect. The jump is powered by large muscles that are found in its thorax and that, in other insects, contribute to both flying and walking movements. These muscles were therefore analysed by transmission electron microscopy to determine whether they have the properties of fast-acting muscle used in flying or those of more slowly acting muscle used in walking. The muscle fibres are arranged in a parallel bundle that inserts onto an umbrella-shaped tendon. The individual fibres have a diameter of about 70 μm and are subdivided into myofibrils a few micrometres in diameter. No variation in ultrastructure was observed in various fibres taken from different parts of the muscle. The sarcomeres are about 15 μm long and the A bands about 10 μm long. The Z lines are poorly aligned within a myofibril. Mitochondrial profiles are sparse and are close to the Z lines. Each thick filament is surrounded by 10-12 thin filaments and the registration of these arrays of filaments is irregular. Synaptic boutons from the two excitatory motor neurons to the muscle fibres are characterised by accumulations of ~60 translucent 40-nm-diameter vesicle profiles per section, corresponding to an estimated 220 vesicles, within a 0.5-μm hemisphere at a presynaptic density. All ultrastructural features conform to those of slow muscle and thus suggest that the muscle is capable of slow sustained contractions in keeping with its known actions during jumping. A fast and powerful movement is thus generated by a slow muscle.
    No preview · Article · Oct 2013 · Cell and Tissue Research
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    Full-text · Dataset · Aug 2013
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    [Show abstract] [Hide abstract] ABSTRACT: Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi-automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations.
    Full-text · Article · Aug 2013 · Nature
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    Full-text · Dataset · Aug 2013
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    Full-text · Dataset · Aug 2013
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    Full-text · Dataset · Aug 2013
  • [Show abstract] [Hide abstract] ABSTRACT: The first Rabbit Retinal Connectome volume (RC1), constructed via automated transmission electron microscopy (ATEM) and computational molecular phenotyping (CMP), spans the mid-inner nuclear layer (INL) at section 001 to the ganglion cell layer (GCL) at section 371, shown in a mirror image below. RC1 is a short cylinder ≈ 250 μm in diameter and ≈ 30 μm high containing 341 ATEM sections and 11 intercalated CMP sections. The cylinder is capped at top and bottom with 10-section CMP series allowing molecular segmentation of cells, and an activity marker, 1-amino-4-guanidobutane (AGB), to mark cells differentially stimulated via glutamatergic synapses. ATEM section 001 is a horizontal plane section through the INL visualized with GABA.glycine.glutamate → red.green.blue transparency mapping and a dark gold alpha channel (ANDed taurine + glutamine channels). ATEM section 371 is a horizontal plane section through the GCL visualized with GABA.AGB.glutamate → red.green.blue transparency mapping.
    No preview · Article · Apr 2013 · The Journal of Comparative Neurology
  • I.A. Meinertzhagen
    [Show abstract] [Hide abstract] ABSTRACT: Introduction. The visual system of the fly's compound eye is noted both for its modular composition and for crystalline regularity. In the compound eye, each module or ommatidium has a fixed complement of 26 cells that includes eight uniquely identified photoreceptor neurons (Ready et al., 1976). An outer ring of six cells, R1-R6, surrounds two central cells R7 and R8 in each ommatidium. Backed by extensive genetic analysis of their development and function, R1-R6 constitute by far the best-understood sensory neurons in any invertebrate visual system, and among the best-known neurons of any nervous system. During its development from the eye imaginal disk, the pattern of ommatidia in the compound eye is impressed upon neurogenesis in the primordia of the underlying optic lobe (Meinertzhagen and Hanson, 1993) and, as a result, the optic lobe neuropiles are likewise modular in their composition, comprising a clear array of cartridges in the first neuropile, the lamina (Braitenberg, 1967) and a less obvious array of columns in the second neuropile, the medulla (Campos-Ortega and Strausfeld, 1972; Strausfeld and Campos-Ortega, 1972). The lamina and medulla are some of the most orderly and well-characterized neuropiles of the entire fly's brain, and models for the brains of all animal species, invertebrate or otherwise. Often overlooked or simply not acknowledged, most essential details of the neuroanatomy of the optic lobe were established not in Drosophila, but in larger fly species - mostly the housefly Musca domestica, before observations on Drosophila became ascendant. Anatomical studies on the optic lobe in Drosophila are, in fact, undergoing an intense renaissance at the time of writing this review, yielding to new genetic and imaging technologies that support a sense of promise that many long-outstanding questions will soon be resolved. Particular issues include the number of individual cell types, their synaptic circuits, and neurotransmitter systems, and whether each type is discrete, distinguishable from all other types. The groundwork for these questions in Drosophila was laid by a commendably accurate report of the cell types derived from Golgi impregnation (Fischbach and Dittrich, 1989), which is still current. Anticipating the topic of this chapter, Meinertzhagen and Hanson (1993) provide summary diagrams of the adult optic lobe that occasional readers have found useful.
    No preview · Article · Jan 2013
  • Kevin Luethy · Shilpa Rawal · Birgit Ahrens · Ian Meinertzhagen · KF Fischbach
    [Show abstract] [Hide abstract] ABSTRACT: Kirre (Kin-of-irre) is a Neph-like member of the evolutionarily conserved IRM protein family (1) with 5 extracellular Ig-domains, a single transmembrane domain and a cytoplasmic tail containing a PDZ-binding domain at its C-terminus. Our studies in Drosophila aim to secure an understanding of the neural function of this protein and we have chosen two paradigms for our investigations: the arborizations of L4 neurons in the optic lamina and the axon terminals of olfactory receptor neurons in the antennal lobe. L4 neurons are the only monopolar cells in each of the synaptic modules, or cartridges of the fly’s lamina that invade two neighboring cartridges via collateral neurites. These collaterals display strong -Kirre immunoreactivity in the proximal lamina, and there L4 neurons form reciprocal synapses with both L2 dendrites and the collaterals from neighbouring L4 neurons. Our light and electron microscopy has shown that the knockdown and knockout of Kirre in L4 neurons selectively reduces synapse numbers. This seems to result from specific defects in target recognition. We now try to generalize these results on target recognition and/or synaptogenesis by investigating Kirre function in the antennal lobes as well. Here olfactory receptor axons display strong -Kirre immunoreactivity. One of the questions we try to answer is whether heterophilic or homophilic trans interactions play a role in the effect of Kirre on synapse number. Homophilic interactions have been reported for Kirrel2 and Kirrel3 in the olfactory system of the mouse (2). Another question involves the degree of redundancy of Kirre with its paralogue Rst (Roughest, 1). Support: DFG Fi336/8-1 (to K-F.F.) and NIH 03592 (to I.A.M.)
    No preview · Conference Paper · Dec 2012

Publication Stats

8k Citations
937.87 Total Impact Points


  • 2013
    • University of Utah
      • John Moran Eye Center
      Salt Lake City, UT, United States
  • 2012
    • Life Science Research Center
      Halifax, Nova Scotia, Canada
  • 1984-1993
    • Dalhousie University
      • Department of Psychology and Neuroscience
      Halifax, Nova Scotia, Canada
  • 1977
    • Harvard University
      Cambridge, Massachusetts, United States