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TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Entwicklungsgenetik Molecular mechanisms that govern the establishment of sensory-motor networks Rosa-Eva Hüttl Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. E. Grill Prüfer der Dissertation: 1. Univ.-Prof. Dr. W. Wurst 2. Univ.-Prof. Dr. H. Luksch Die Dissertation wurde am 08.12.2011 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 27.02.2012 angenommen. Erklärung Hiermit erkläre ich an Eides statt, dass ich die der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Promotionsprüfung vorgelegte Arbeit mit dem Titel „Molecular mechanisms that govern the establishment of sensory-motor networks“ am Lehrstuhl für Entwicklungsgenetik unter der Anleitung und Betreuung durch Univ.-Prof. Dr. Wolfgang Wurst ohne sonstige Hilfe erstellt und bei der Abfassung nur die gemäß § 6 Abs. 5 angegebenen Hilfsmittel benutzt habe. Ich habe keine Organisation eingeschaltet, die gegen Entgelt Betreuerinnen und Betreuer für die Anfertigung von Dissertationen sucht, oder die mir obliegenden Pflichten hinsichtlich der Prüfungsleistung für mich ganz oder teilweise erledigt. Ich habe die Dissertation in dieser oder ähnlicher Form keinem anderen Prüfungsverfahren als Prüfungsleistung vorgelegt. Ich habe den angestrebten Doktortitel noch nicht erworben und bin nicht in einem früheren Promotionsverfahren für den angestrebten Doktorgrad endgültig gescheitert. Die Promotionsordnung der Technischen Universität München ist mir bekannt. München, den ______________ __________________________ Rosa-Eva Hüttl a ABSTRACT During the development of the vertebrate nervous system, motor projections that activate muscles in the extremities and sensory afferents delivering feedback to the motor neurons about posture and other sensations need to be assembled to precisely integrated circuitries. Only then, the initiation, execution and completion of complex locomotor behaviors are feasible. Projections to peripheral targets are established in a stepwise process that is spatially and temporally tightly controlled, however, while some basic principles of axon guidance are well established, the molecular mechanisms and cues governing sensory-motor co-extension, inter-axonal communication and axon-glia interactions are not well understood. The goal of my PhD project was to investigate the molecular mechanisms that govern the establishment of sensory-motor networks. I used cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motor neurons or sensory neurons in the dorsal root ganglia (DRG) to explore the contribution of this signaling pathway to the correct innervation of the limb. We show that Npn-1 controls fasciculation of both motor and sensory projections, as well as communication between sensory and motor trajectories at crucial choice points during axon extension. Removal of Npn-1 from sensory neurons lifts the tight coupling of sensory axon growth on previously extended motor axons, thus resulting in sensory axons leading the spinal nerve projection. Interestingly, defasciculation of sensory axons is accompanied by defasciculation of motor axons before and after the plexus region. Deletion of Npn-1 from motor neurons leads to severe defasciculation of motor axons in the distal limb and errors in the dorsal-ventral guidance decision, while pre-plexus fasciculation, as well as patterning and fasciculation of sensory projections in the distal limb remain unaffected. Thus, we found that motor and sensory axons are dependent on each other for the generation of their trajectories and partially interact through Npn-1 to mediate axon coupling and fasciculation of spinal nerves before and within the plexus region of the limb. Also at cranial levels, Npn-1 is expressed in motor neurons and sensory ganglia. Loss of Sema3A–Npn-1 signaling leads to defasciculation of the superficial projections to the head and neck. However, as these are mixed sensory-motor 1 projections, it was unclear whether Npn-1 is required in both neuronal populations for proper distal nerve assembly and fasciculation. Furthermore, the molecular mechanisms that govern the initial fasciculation and growth of the pure motor projections of the hypoglossal and abducens nerves in general, and the role of Npn-1 in these processes in particular were unclear. We show here that ablation of Npn-1 specifically from cranial neural crest and placodally derived sensory tissues recapitulates the distal defasciculation of the trigeminal, facial, glossopharyngeal and vagal projections, that was observed in Npn-1−/− mutants and in mice where binding of Npn-1 to all class 3 Semaphorins was abolished (Npn-1Sema−). Selective removal of Npn-1 from somatic motor neurons impairs the initial fasciculation and assembly of hypoglossal rootlets and leads to reduced numbers of abducens and hypoglossal fibers. Surprisingly, assembly and fasciculation of the hypoglossal nerve that consists exclusively of somatic motor axons are also impaired when Npn-1 was ablated in sensory tissues. The defects in initial fasciculation are accompanied by a decrease of neural crest derived Schwann cells migrating along hypoglossal rootlets. These findings were corroborated by partial genetic elimination of cranial neural crest and embryonic placodes: we found aberrant growth patterns of the hypoglossal nerve after the loss of neural crest derived Schwann cell precursors. Interestingly, rostral turning of hypoglossal axons is not perturbed in any of the investigated genotypes. Our results therefore emphasise the crucial role of Sema3A-Npn-1 signaling for selective fasciculation of motor and sensory projections during cranial nerve extension. Furthermore, our data suggest that somatic motor nerve fasciculation at cranial levels depend on Npn-1 expression and axon-Schwann cell interactions in developing vertebrates. Several ligand-receptor interactions have been identified that critically contribute to the establishment of neuronal projections to the limb and mediate the stereotypic dorsal-ventral guidance decisions of growing motor axons at the base of the limb. However, these interactions cannot explain exhaustively how correct wiring of the motor system is achieved during development, as single or compound mutant embryos do not show a complete deregulation of motor axon guidance. For sensory neurons of the DRG, no guidance cues facilitating dorsal or ventral sensory axon guidance decisions have been identified so far. Classical ablation experiments in chicken suggested that sensory axons only depend on correctly laid out motor projections for proper guidance to peripheral targets. However, we showed that 2 sensory axons are capable to establish correct growth patterns even when distal motor projections are severely defasciculated or absent. These findings implicate specific guidance also of sensory axons. Our group employed a genome wide expression profiling using microarray technique to identify novel molecules involved in the guidance of motor and sensory axons to the dorsal or ventral limb. Using in situ hybridization and immunohistochemistry, we validated the expression patterns of four candidate genes that were predicted to be differentially expressed in brachial motor neurons at E12.5. The functions of the candidate genes Arhgap29 and Ccdc3 during development have not been characterized until now. However, these genes show a patterned expression already between E10.5 and E11.5, when motor axons navigate the dorsal-ventral choice point, and might therefore contribute to the topographic organization of motor projections. The ETS transcription factor Elk3 is expressed differentially in ventrally projecting motor neurons only at E12.5. At E11.5, the transcription factor is expressed uniformly in both dorsally and ventrally projecting motor neurons, and shows no expression at E10.5. Therefore, differential expression of Elk3 was only found at a time when the dorsal-ventral decision point has already been navigated. Still, as a close relative to genes of the ETS gene family, it might nevertheless have a function in the definition of motor neuron pools innervating the same target musculature. Fgfr2-signaling is essential for early rostro-caudal motor neuron patterning and limb bud induction, however, its role in motor nerves innervating the extremities has not been assessed up to now. I confirmed the predicted differential expression with higher expression levels in ventrally projecting LMC neurons and employed a conditional approach to selectively remove Fgfr2 from spinal motor neurons. We found that Fgfr2 expression in spinal motor neurons is dispensable for fasciculation, distal advancement and general growth patterns of motor axons to the distal limb. As mentioned above, up to now, no markers exist to distinguish sensory neurons according to their topographic projections in the periphery. We confirmed the predicted differential expression for five genes and found them to be predominantly, but not exclusively expressed in dorsally projecting sensory neurons that were retrogradely labeled from dorsal limb mesenchyme: Cux2, Gnb4, Ift172, Nek1 and PLCd4. Further investigations
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