Neural development and wiring

Currently, we have open positions for Diploma and PhD students interested in developmental neurobiology. 

Please send your application, which should include a cover letter and a CV, by email to: christian.soellner[at]tuebingen.mpg.de

Introduction

The establishment of a complex neuronal network such as the vertebrate brain requires intricate cell-cell communication events. Intercellular recognition and communication is essential for cell specification, migration, neurite navigation, target selection, and synapse formation. Signals between cells are typically received and sent by cell-surface and secreted (CSS) proteins.

To get a better understanding of these cell-cell communication events we are aiming to identify new neuronal CSS receptor-ligand pairs and analyse their function during early brain development and wiring. We employ a recently developed avidity-based extracellular interaction screen assay (AVEXIS) to detect extracellular protein interactions and integrate the results with the spatio-temporal expression patterns of the corresponding genes to generate informative tissue and stage specific subnetworks. These subnetworks serve as frameworks for systematic functional validation in zebrafish, a vertebrate model organism ideal for imaging and with well established embryological and genetic techniques.

 A central brain nucleus as a model to study cell-cell communication events

The nucleus of the medial longitudinal fascicle (nMLF) is a cluster of very early differentiating neurons. These neurons are located bilaterally and symmetrically in the ventral midbrain close to the midline. Their axons pioneer the pathway of the medial longitudinal fascicle (MLF), one of the earliest axon tracts to form in the developing central nervous system (Fig. 1a). Two main populations of neurons, medial-medial and medial-lateral, each having specific morphologies, have been described to constitute the nMLF (Fig.1b,c).

Fig.1:  Schematic dorsal view drawings of the nMLF and morphologies of its neuronal subtypes. A, anterior; HB, hindbrain; MeM, medial-medial neuron; MeL, medial-lateral neuron; MLF, medial longitudinal fascicle; nMLF, nucleus of the medial longitudinal fascicle; P, posterior; SC, spinal cord.

nMLF neurons together with other spinal projection neurons ensure that the processing of sensory information in the brain gets transmitted to the spinal cord and initiates the appropriate behavioural motor output.

Although conserved in vertebrates, surprisingly little is known about the cell-surface interactions which are involved in the specification and differentiation of the nMLF neurons and about the signalling pathways, which guide the axons and dendrites of the nMLF to their appropriate targets.

This central brain nucleus represents a relatively simple accessible functional unit, to study many aspects of neuronal development and circuit formation in living zebrafish embryos.

A nMLF receptor network

Previous large-scale extracellular protein interaction screens, carried out at the Sanger Institute (Cambridge, UK), led to the identification of 188 interactions among 92 proteins. Systematic analysis of the spatio-temporal expression patterns of the genes encoding interacting proteins allowed to compile a nMLF cell-surface receptor protein interaction network. This nMLF receptor network (nMLFnet) comprises 32 proteins forming 36 interactions. They are either expressed in the neurons of the nMLF, the adjacent floor plate, or less restricted in the ventral midbrain (Fig.2).

 Fig.2: Examples of nMLFnet gene expression patterns. Each image shows the expression of two genes whose proteins have been identified to interact. a) depicts the nMLF in a 24 hours post fertilisation (hpf) embryo, b)-c) show the midbrain region of 28hpf embryos.  All images are dorsal views. Anterior is to the left. FP, floor plate; nMLF, nucleus of the medial longitudinal fascicle; MLF, medial longitudinal fascicle; VZ, ventricular zone.

Current research projects aim to determine the in vivo function of nMLFnet interactions in zebrafish. In order to do so we are starting to use 4-D imaging which will allow to monitor the behaviour of nMLF neurons during the establishment of their neuronal network and to compare this dynamic process in wild type and genetically modified zebrafish embryos.

Long-term aim: Expand nMLF interaction network

We are planning to identify additional CSS protein encoding genes expressed in the nMLF, floor plate, or ventral midbrain and use them to test for pairwise physical interactions in an AVEXIS based assay. This will lead to an expanded nMLF extracellular space interaction network. Ultimately, this will bring us closer to a systems-level understanding of the cell-cell and cell-extracellular-matrix communication events governing nMLF development and wiring.

Personnel

Dr. Christian Söllner                                               Project leader (04/09 - )

Hans-Martin Maischein 

Publications

Obholzer, N., Wolfson, S., Trapani, J., Mo, W., Nechipourak, A., Busch-Nentwich, E., Seiler, C., Sidi, S., Söllner, C., Duncan, R., Boehland, A., & Nicolson, T. Vesicular glutamate transporter 3 is required for synaptic transmission in zebrafish hair cells. J Neurosci. 28(9), 2110 (2008).

Bushell, K. M., Söllner, C., Schuster-Boeckler, B., Bateman, A., & Wright, G.J. Large scale screening for novel low affinity extracellular protein interactions. Genome Res. 18, 622 (2008).

Geisler, R., Rauch, G.J., Geiger-Rudolph, S., Albrecht, A., van Bebber, F., Berger, A., Busch-Nentwich, E., Dahm, R., Dekens, M.P., Dooley, C., Elli, A.F., Gehring, I., Geiger, H., Geisler, M., Glaser, S., Holley, S., Huber, M., Kerr, A., Kirn, A., Knirsch, M., Konantz, M., Kuchler, A.M., Maderspacher, F., Neuhauss, S.C., Nicolson, T., Ober, E.A., Praeg, E., Ray, R., Rentzsch, B., Rick, J.M., Rief, E., Schauerte, H.E., Schepp, C.P., Schonberger, U., Schonthaler, H.B., Seiler, C., Sidi, S., Söllner, C., Wehner, A., Weiler, C., & Nüsslein-Volhard, C. Large-scale mapping of mutations affecting zebrafish development. BMC Genomics. 9;8:11 (2007).

Söllner, C., Schwarz, H., Geisler, R., & Nicolson, T. Mutated otopetrin 1 affects the genesis of otoliths and the localization of Starmaker in zebrafish. Dev Genes Evol. 214(12), 582 (2004).

Söllner, C., Rauch, G.J., Siemens, J., Geisler, R., Schuster, S., The Tübingen 2000 Screen Consortium, Müller, U., & Nicolson, T. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells. Nature 428, 955 (2004).

Busch-Nentwich, E., Söllner, C., Roel, H., & Nicolson, T. The deafness gene dfna5 is crucial for ugdh expression and HA production in the developing ear in zebrafish. Development 131, 943 (2004).

Söllner, C., Burghammer, M., Busch-Nentwich, E., Berger, J., Schwarz, H., Riekel, C., & Nicolson, T. Control of crystal size and lattice formation by starmaker during otolith biomineralization. Science 302, 282 (2003).

Reviews and Book Chapters

Lee, C., Bongcam-Rudolf, E., Söllner, C., Jahnen-Dechent, W., and Claesson-Welsh, L. Type 3 Cystatins; fetuins, kininogen and histidine-rich glycoprotein. Front Biosci. 1;14:2911 (2009).

Söllner, C., Nicolson, T. The zebrafish as a genetic model to study otolith formation. In: “Biomineralization: Progress in Biology, Molecular Biology and Application” (E. Bäuerlein, ed.); Wiley-VCH, New York; (2004).