Julia Kaltschmidt

All Publications

• Sensory and descending motor circuitry during development and injury. Current opinion in neurobiology Plant, G. W., Weinrich, J. A., Kaltschmidt, J. A. 2018; 53: 156–61

  Abstract

  Proprioceptive sensory input and descending supraspinal projections are two major inputs that feed into and influence spinal circuitry and locomotor behaviors. Here we review their influence on each other during development and after spinal cord injury. We highlight developmental mechanisms of circuit formation as they relate to the sensory-motor circuit and its reciprocal interactions with local spinal interneurons, as well as competitive interactions between proprioceptive and descending supraspinal inputs in the setting of spinal cord injury.

  View details for DOI 10.1016/j.conb.2018.08.008

  View details for PubMedID 30205323

• A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry. Cell reports Zhang, J., Weinrich, J. A., Russ, J. B., Comer, J. D., Bommareddy, P. K., DiCasoli, R. J., Wright, C. V., Li, Y., van Roessel, P. J., Kaltschmidt, J. A. 2017; 21 (3): 666–78

  Abstract

  Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted, formation of GABApre sensory afferent synapses is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.

  View details for DOI 10.1016/j.celrep.2017.09.079

  View details for PubMedID 29045835

• Satb2 Stations Neurons along Reflex Arcs NEURON Hantman, A. W., Kaltschmidt, J. A. 2016; 91 (4): 711-713

  Abstract

  The nociceptive flexor withdrawal reflex has an august place in the history of neuroscience. In this issue of Neuron, Hilde et al. (2016) advance our understanding of this reflex by characterizing the molecular identity and circuit connectivity of component interneurons. They assess how a DNA-binding factor Satb2 controls cell position, molecular identity, pre-and postsynaptic targeting, and function of a population of inhibitory sensory relay interneurons that serve to integrate both proprioceptive and nociceptive afferent information.

  View details for DOI 10.1016/j.neuron.2016.08.005

  View details for Web of Science ID 000382396700001

  View details for PubMedID 27537478

• Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord NEURON Mende, M., Fletcher, E. V., Belluardo, J. L., Pierce, J. P., Bommareddy, P. K., Weinrich, J. A., Kabir, Z. D., Schierberl, K. C., Pagiazitis, J. G., Mendelsohn, A. I., Francesconi, A., Edwards, R. H., Milner, T. A., Rajadhyaksha, A. M., van Roessel, P. J., Mentis, G. Z., Kaltschmidt, J. A. 2016; 90 (6): 1189-1202

  Abstract

  Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis.

  View details for DOI 10.1016/j.neuron.2016.05.008

  View details for Web of Science ID 000378527600009

  View details for PubMedID 27263971

  View details for PubMedCentralID PMC4912012

• Normal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1 JOURNAL OF NEUROSCIENCE Law, C., Profes, M. S., Levesque, M., Kaltschmidt, J. A., Verhage, M., Kania, A. 2016; 36 (2): 561-576

  Abstract

  The role of synaptic activity during early formation of neural circuits is a topic of some debate; genetic ablation of neurotransmitter release by deletion of the Munc18-1 gene provides an excellent model to answer the question of whether such activity is required for early circuit formation. Previous analysis of Munc18-1(-/-) mouse mutants documented their grossly normal nervous system, but its molecular differentiation has not been assessed. Munc18-1 deletion in mice also results in widespread neurodegeneration that remains poorly characterized. In this study, we demonstrate that the early stages of spinal motor circuit formation, including motor neuron specification, axon growth and pathfinding, and mRNA expression, are unaffected in Munc18-1(-/-) mice, demonstrating that synaptic activity is dispensable for early nervous system development. Furthermore, we show that the neurodegeneration caused by Munc18-1 loss is cell autonomous, consistent with apparently normal expression of several neurotrophic factors and normal GDNF signaling. Consistent with cell-autonomous degeneration, we demonstrate defects in the trafficking of the synaptic proteins Syntaxin1a and PSD-95 and the TrkB and DCC receptors in Munc18-1(-/-) neurons; these defects do not appear to cause ER stress, suggesting other mechanisms for degeneration. Finally, we demonstrate pathological similarities to Alzheimer's disease, such as altered Tau phosphorylation, neurofibrillary tangles, and accumulation of insoluble protein plaques. Together, our results shed new light upon the neurodegeneration observed in Munc18-1(-/-) mice and argue that this phenomenon shares parallels with neurodegenerative diseases.In this work, we demonstrate the absence of a requirement for regulated neurotransmitter release in the assembly of early neuronal circuits by assaying transcriptional identity, axon growth and guidance, and mRNA expression in Munc18-1-null mice. Furthermore, we characterize the neurodegeneration observed in Munc18-1 mutants and demonstrate that this cell-autonomous process does not appear to be a result of defects in growth factor signaling or ER stress caused by protein trafficking defects. However, we find the presence of various pathological hallmarks of Alzheimer's disease that suggest parallels between the degeneration in these mutants and neurodegenerative conditions.

  View details for DOI 10.1523/JNEUROSCI.1964-15.2016

  View details for Web of Science ID 000368352600027

  View details for PubMedID 26758845

• Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3 FRONTIERS IN NEURAL CIRCUITS Comer, J. D., Pan, F. C., Willet, S. G., Haldipur, P., Millen, K. J., Wright, C. V., Kaltschmidt, J. A. 2015; 9

  Abstract

  Commissural neurons project across the midline at all levels of the central nervous system (CNS), providing bilateral communication critical for the coordination of motor activity and sensory perception. Midline crossing at the spinal ventral midline has been extensively studied and has revealed that multiple developmental lineages contribute to this commissural neuron population. Ventral midline crossing occurs in a manner dependent on Robo3 regulation of Robo/Slit signaling and the ventral commissure is absent in the spinal cord and hindbrain of Robo3 mutants. Midline crossing in the spinal cord is not limited to the ventral midline, however. While prior anatomical studies provide evidence that commissural axons also cross the midline dorsally, little is known of the genetic and molecular properties of dorsally-crossing neurons or of the mechanisms that regulate dorsal midline crossing. In this study, we describe a commissural neuron population that crosses the spinal dorsal midline during the last quarter of embryogenesis in discrete fiber bundles present throughout the rostrocaudal extent of the spinal cord. Using immunohistochemistry, neurotracing, and mouse genetics, we show that this commissural neuron population includes spinal inhibitory neurons and sensory nociceptors. While the floor plate and roof plate are dispensable for dorsal midline crossing, we show that this population depends on Robo/Slit signaling yet crosses the dorsal midline in a Robo3-independent manner. The dorsally-crossing commissural neuron population we describe suggests a substrate circuitry for pain processing in the dorsal spinal cord.

  View details for DOI 10.3389/fncir.2015.00036

  View details for Web of Science ID 000359749600001

  View details for PubMedID 26257608

• Misexpression of Ptf1a in Cortical Pyramidal Cells In Vivo Promotes an Inhibitory Peptidergic Identity JOURNAL OF NEUROSCIENCE Russ, J. B., Borromeo, M. D., Kollipara, R. K., Bommareddy, P. K., Johnson, J. E., Kaltschmidt, J. A. 2015; 35 (15): 6028-6037

  Abstract

  The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al., 2008), retina (Fujitani et al., 2006; Dullin et al., 2007; Nakhai et al., 2007; Lelièvre et al., 2011), and cerebellum (Hoshino et al., 2005; Pascual et al., 2007; Yamada et al., 2014), where it promotes an inhibitory over an excitatory neuronal identity. In this study, we investigate the potency of Ptf1a to cell autonomously confer a specific neuronal identity outside of its endogenous environment, using mouse in utero electroporation and a conditional genetic strategy to misexpress Ptf1a exclusively in developing cortical pyramidal cells. Transcriptome profiling of Ptf1a-misexpressing cells using RNA-seq reveals that Ptf1a significantly alters pyramidal cell gene expression, upregulating numerous Ptf1a-dependent inhibitory interneuron markers and ultimately generating a gene expression profile that resembles the transcriptomes of both Ptf1a-expressing spinal interneurons and endogenous cortical interneurons. Using RNA-seq and in situ hybridization analyses, we also show that Ptf1a induces expression of the peptidergic neurotransmitter nociceptin, while minimally affecting the expression of genes linked to other neurotransmitter systems. Moreover, Ptf1a alters neuronal morphology, inducing the radial redistribution and branching of neurites in cortical pyramidal cells. Thus Ptf1a is sufficient, even in a dramatically different neuronal precursor, to cell autonomously promote characteristics of an inhibitory peptidergic identity, providing the first example of a single transcription factor that can direct an inhibitory peptidergic fate.

  View details for DOI 10.1523/JNEUROSCI.3821-14.2015

  View details for Web of Science ID 000353055600015

  View details for PubMedID 25878276

• From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity OPEN BIOLOGY Russ, J. B., Kaltschmidt, J. A. 2014; 4 (10)

  Abstract

  Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

  View details for DOI 10.1098/rsob.140144

  View details for Web of Science ID 000347899600007

  View details for PubMedID 25297387

• Neuronal Ig/Caspr Recognition Promotes the Formation of Axoaxonic Synapses in Mouse Spinal Cord NEURON Ashrafi, S., Betley, J. N., Comer, J. D., Brenner-Morton, S., Bar, V., Shimoda, Y., Watanabe, K., Peles, E., Jessell, T. M., Kaltschmidt, J. A. 2014; 81 (1): 120-129

  Abstract

  Inhibitory microcircuits are wired with a precision that underlies their complex regulatory roles in neural information processing. In the spinal cord, one specialized class of GABAergic interneurons (GABApre) mediates presynaptic inhibitory control of sensory-motor synapses. The synaptic targeting of these GABAergic neurons exhibits an absolute dependence on proprioceptive sensory terminals, yet the molecular underpinnings of this specialized axoaxonic organization remain unclear. Here, we show that sensory expression of an NB2 (Contactin5)/Caspr4 coreceptor complex, together with spinal interneuron expression of NrCAM/CHL1, directs the high-density accumulation of GABAergic boutons on sensory terminals. Moreover, genetic elimination of NB2 results in a disproportionate stripping of inhibitory boutons from high-density GABApre-sensory synapses, suggesting that the preterminal axons of GABApre neurons compete for access to individual sensory terminals. Our findings define a recognition complex that contributes to the assembly and organization of a specialized GABAergic microcircuit.

  View details for DOI 10.1016/j.neuron.2013.10.060

  View details for Web of Science ID 000329559000013

  View details for PubMedID 24411736

• Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord FRONTIERS IN NEURAL CIRCUITS Russ, J. B., Verina, T., Comer, J. D., Comi, A. M., Kaltschmidt, J. A. 2013; 7

  Abstract

  During perinatal development, corticospinal tract (CST) projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit. We found that putative GABApre interneurons receive CST input and, using an established mouse model of perinatal stroke, that cortical ischemic injury results in a reduction of CST density within the intermediate region of the spinal cord, where these interneurons reside. Importantly, CST alterations were restricted to the side contralateral to the injury. Within the synaptic terminals of the GABApre interneurons, we observed a dramatic upregulation of the 65-isoform of the GABA synthetic enzyme glutamic acid decarboxylase (GAD65). In accordance with the CST density reduction, GAD65 was elevated on the side of the spinal cord contralateral to cortical injury. This effect was not seen for other GABApre synaptic markers or in animals that received sham surgery. Our data reveal a novel effect of perinatal stroke that involves severe deficits in the architecture of a descending spinal pathway, which in turn appear to promote molecular alterations in a specific spinal GABAergic circuit.

  View details for DOI 10.3389/fncir.2013.00150

  View details for Web of Science ID 000324807700001

  View details for PubMedID 24093008

• Wnt7A identifies embryonic ?-motor neurons and reveals early postnatal dependence of ?-motor neurons on a muscle spindle-derived signal. journal of neuroscience Ashrafi, S., Lalancette-Hébert, M., Friese, A., Sigrist, M., Arber, S., Shneider, N. A., Kaltschmidt, J. A. 2012; 32 (25): 8725-8731

  Abstract

  Motor pools comprise a heterogeneous population of motor neurons that innervate distinct intramuscular targets. While the organization of motor neurons into motor pools has been well described, the time course and mechanism of motor pool diversification into functionally distinct classes remains unclear. γ-Motor neurons (γ-MNs) and α-motor neurons (α-MNs) differ in size, molecular identity, synaptic input and peripheral target. While α-MNs innervate extrafusal skeletal muscle fibers to mediate muscle contraction, γ-MNs innervate intrafusal fibers of the muscle spindle, and regulate sensitivity of the muscle spindle in response to stretch. In this study, we find that the secreted signaling molecule Wnt7a is selectively expressed in γ-MNs in the mouse spinal cord by embryonic day 17.5 and continues to molecularly distinguish γ-from α-MNs into the third postnatal week. Our data demonstrate that Wnt7a is the earliest known γ-MN marker, supporting a model of developmental divergence between α- and γ-MNs at embryonic stages. Furthermore, using Wnt7a expression as an early marker of γ-MN identity, we demonstrate a previously unknown dependence of γ-MNs on a muscle spindle-derived, GDNF-independent signal during the first postnatal week.

  View details for DOI 10.1523/JNEUROSCI.1160-12.2012

  View details for PubMedID 22723712

• Stringent Specificity in the Construction of a GABAergic Presynaptic Inhibitory Circuit CELL Betley, J. N., Wright, C. V., Kawaguchi, Y., Erdelyi, F., Szabo, G., Jessell, T. M., Kaltschmidt, J. A. 2009; 139 (1): 161-174

  Abstract

  GABAergic interneurons are key elements in neural coding, but the mechanisms that assemble inhibitory circuits remain unclear. In the spinal cord, the transfer of sensory signals to motor neurons is filtered by GABAergic interneurons that act presynaptically to inhibit sensory transmitter release and postsynaptically to inhibit motor neuron excitability. We show here that the connectivity and synaptic differentiation of GABAergic interneurons that mediate presynaptic inhibition is directed by their sensory targets. In the absence of sensory terminals these GABAergic neurons shun other available targets, fail to undergo presynaptic differentiation, and withdraw axons from the ventral spinal cord. A sensory-specific source of brain derived neurotrophic factor induces synaptic expression of the GABA synthetic enzyme GAD65--a defining biochemical feature of this set of interneurons. The organization of a GABAergic circuit that mediates presynaptic inhibition in the mammalian CNS is therefore controlled by a stringent program of sensory recognition and signaling.

  View details for DOI 10.1016/j.cell.2009.08.027

  View details for Web of Science ID 000270388600024

  View details for PubMedID 19804761

• Gamma and alpha motor neurons distinguished by expression of transcription factor Err3 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Friese, A., Kaltschmidt, J. A., Ladle, D. R., Sigrist, M., Jessell, T. M., Arber, S. 2009; 106 (32): 13588-13593

  Abstract

  Spinal motor neurons are specified to innervate different muscle targets through combinatorial programs of transcription factor expression. Whether transcriptional programs also establish finer aspects of motor neuron subtype identity, notably the prominent functional distinction between alpha and gamma motor neurons, remains unclear. In this study, we identify DNA binding proteins with complementary expression profiles in alpha and gamma motor neurons, providing evidence for molecular distinctions in these two motor neuron subtypes. The transcription factor Err3 is expressed at high levels in gamma but not alpha motor neurons, whereas the neuronal DNA binding protein NeuN marks alpha but not gamma motor neurons. Signals from muscle spindles are needed to support the differentiation of Err3(on)/NeuN(off) presumptive gamma motor neurons, whereas direct proprioceptive sensory input to a motor neuron pool is apparently dispensable. Together, these findings provide evidence that transcriptional programs define functionally distinct motor neuron subpopulations, even within anatomically defined motor pools.

  View details for DOI 10.1073/pnas.0906809106

  View details for Web of Science ID 000268877300079

  View details for PubMedID 19651609

• Conditional rhythmicity of ventral spinal interneurons defined by expression of the Hb9 homeodomain protein JOURNAL OF NEUROSCIENCE Wilson, J. M., Hartley, R., Maxwell, D. J., Todd, A. J., Lieberam, I., Kaltschmidt, J. A., Yoshida, Y., Jessell, T. M., Brownstone, R. M. 2005; 25 (24): 5710-5719

  Abstract

  The properties of mammalian spinal interneurons that underlie rhythmic locomotor networks remain poorly described. Using postnatal transgenic mice in which expression of green fluorescent protein is driven by the promoter for the homeodomain transcription factor Hb9, as well as Hb9-lacZ knock-in mice, we describe a novel population of glutamatergic interneurons located adjacent to the ventral commissure from cervical to midlumbar spinal cord levels. Hb9+ interneurons exhibit strong postinhibitory rebound and demonstrate pronounced membrane potential oscillations in response to chemical stimuli that induce locomotor activity. These data provide a molecular and physiological delineation of a small population of ventral spinal interneurons that exhibit homogeneous electrophysiological features, the properties of which suggest that they are candidate locomotor rhythm-generating interneurons.

  View details for DOI 10.1523/JNEUROSCI.0274-05.2005

  View details for Web of Science ID 000229815700006

  View details for PubMedID 15958737

• Polar transport in the Drosophilia oocyte requires Dynein and Kinesin I cooperation CURRENT BIOLOGY Januschke, J., Gervais, L., Dass, S., Kaltschmidt, J. A., Lopez-Schier, H., St Johnston, D., Brand, A. H., Roth, S., Guichet, A. 2002; 12 (23): 1971-1981

  Abstract

  The cytoskeleton and associated motors play an important role in the establishment of intracellular polarity. Microtubule-based transport is required in many cell types for the asymmetric localization of mRNAs and organelles. A striking example is the Drosophila oocyte, where microtubule-dependent processes govern the asymmetric positioning of the nucleus and the localization to distinct cortical domains of mRNAs that function as cytoplasmic determinants. A conserved machinery for mRNA localization and nuclear positioning involving cytoplasmic Dynein has been postulated; however, the precise role of plus- and minus end-directed microtubule-based transport in axis formation is not yet understood.Here, we show that mRNA localization and nuclear positioning at mid-oogenesis depend on two motor proteins, cytoplasmic Dynein and Kinesin I. Both of these microtubule motors cooperate in the polar transport of bicoid and gurken mRNAs to their respective cortical domains. In contrast, Kinesin I-mediated transport of oskar to the posterior pole appears to be independent of Dynein. Beside their roles in RNA transport, both motors are involved in nuclear positioning and in exocytosis of Gurken protein. Dynein-Dynactin complexes accumulate at two sites within the oocyte: around the nucleus in a microtubule-independent manner and at the posterior pole through Kinesin-mediated transport.The microtubule motors cytoplasmic Dynein and Kinesin I, by driving transport to opposing microtubule ends, function in concert to establish intracellular polarity within the Drosophila oocyte. Furthermore, Kinesin-dependent localization of Dynein suggests that both motors are components of the same complex and therefore might cooperate in recycling each other to the opposite microtubule pole.

  View details for Web of Science ID 000179954200014

  View details for PubMedID 12477385

• Planar polarity and actin dynamics in the epidermis of Drosophila NATURE CELL BIOLOGY Kaltschmidt, J. A., Lawrence, N., Morel, V., Balayo, T., Fernandez, B. G., Pelissier, A., Jacinto, A., Arias, A. M. 2002; 4 (12): 937-944

  Abstract

  Dorsal closure is a morphogenetic process involving the coordinated convergence of two epithelial sheets to enclose the Drosophila melanogaster embryo. Specialized populations of cells at the edges of each epithelial sheet, the dorsal-most epidermal cells, emit actin-based processes that are essential for the proper enclosure of the embryo. Here we show that actin dynamics at the leading edge is preceded by a planar polarization of the dorsal-most epidermal cells associated with a reorganization of the cytoskeleton. An important consequence of this planar polarization is the formation of actin-nucleating centres at the leading edge, which are important in the dynamics of actin. We show that Wingless (Wg) signalling and Jun amino-terminal kinase (JNK) signalling have overlapping but different roles in these events.

  View details for DOI 10.1038/ncb882

  View details for Web of Science ID 000179571800013

  View details for PubMedID 12447392

• A new dawn for an old connection: development meets the cell TRENDS IN CELL BIOLOGY Kaltschmidt, J. A., Arias, A. M. 2002; 12 (7): 316-320

  Abstract

  Increasingly, the attention of developmental biologists is being drawn from genes and their products towards cells, from processes mediated by linear pathways in which one protein regulates the activity of another to events that rely on multimolecular machines. Some components of these machines are partially redundant, and some have essential functions in general cellular processes. These observations invite a reassessment of the uses of genetics for analyzing the cell biology of development. In addition, the increasing ability to image live cells and their proteins reveals a complex and interesting world, forcing us to deal with new variables and objects of study. Here, we provide a glimpse of these changes and the challenges they raise.

  View details for Web of Science ID 000176365200007

  View details for PubMedID 12185848

• Asymmetric cell division: microtubule dynamics and spindle asymmetry JOURNAL OF CELL SCIENCE Kaltschmidt, J. A., Brand, A. H. 2002; 115 (11): 2257-2264

  Abstract

  Asymmetric cell division can produce daughter cells with different developmental fates and is often accompanied by a difference in cell size. A number of recent genetic and in vivo imaging studies in Drosophila and Caenorhabditis elegans have begun to elucidate the mechanisms underlying the rearrangements of the cytoskeleton that result in eccentrically positioned cleavage planes. As a result, we are starting to gain an insight into the complex nature of the signals controlling cytoskeletal dynamics in the dividing cell. In this commentary we discuss recent findings on how the mitotic spindle is positioned and on cleavage site induction and place them in the context of cell size asymmetry in different model organisms.

  View details for Web of Science ID 000176450900001

  View details for PubMedID 12006610

• Frizzled regulates localization of cell-fate determinants and mitotic spindle rotation during asymmetric cell division NATURE CELL BIOLOGY Bellaiche, Y., Gho, M., Kaltschmidt, J. A., Brand, A. H., Schweisguth, F. 2001; 3 (1): 50-57

  Abstract

  Cell-fate diversity is generated in part by the unequal segregation of cell-fate determinants during asymmetric cell divisions. In the Drosophila pupa, the pI sense organ precursor cell is polarized along the anterior-posterior axis of the fly and divides asymmetrically to generate a posterior pIIa cell and an anterior pIIb cell. The anterior pIIb cell specifically inherits the determinant Numb and the adaptor protein Partner of Numb (Pon). By labelling both the Pon crescent and the microtubules in living pupae, we show that determinants localize at the anterior cortex before mitotic-spindle formation, and that the spindle forms with random orientation and rotates to line up with the Pon crescent. By imaging living frizzled (fz) mutant pupae we show that Fz regulates the orientation of the polarity axis of pI, the initiation of spindle rotation and the unequal partitioning of determinants. We conclude that Fz participates in establishing the polarity of pI.

  View details for Web of Science ID 000166146400020

  View details for PubMedID 11146626

• Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system NATURE CELL BIOLOGY Kaltschmidt, J. A., Davidson, C. M., Brown, N. H., Brand, A. H. 2000; 2 (1): 7-12

  Abstract

  The asymmetric segregation of cell-fate determinants and the generation of daughter cells of different sizes rely on the correct orientation and position of the mitotic spindle. In the Drosophila embryo, the determinant Prospero is localized basally and is segregated equally to daughters of similar cell size during epidermal cell division. In contrast, during neuroblast division Prospero is segregated asymmetrically to the smaller daughter cell. This simple switch between symmetric and asymmetric segregation is achieved by changing the orientation of cell division: neural cells divide in a plane perpendicular to that of epidermoblast division. Here, by labelling mitotic spindles in living Drosophila embryos, we show that neuroblast spindles are initially formed in the same axis as epidermal cells, but rotate before cell division. We find that daughter cells of different sizes arise because the spindle itself becomes asymmetric at anaphase: apical microtubules elongate, basal microtubules shorten, and the midbody moves basally until it is positioned asymmetrically between the two spindle poles. This observation contradicts the widely held hypothesis that the cleavage furrow is always placed midway between the two centrosomes.

  View details for Web of Science ID 000084843600012

  View details for PubMedID 10620800