Migratory pathways and neuritic differentiation of inferior olivary neurons in the rat embryo. Axonal tracing study using the in vitro slab technique

Climbing fiber (CF) neurons in the inferior olivary nucleus (ION) extend their axons to Purkinje cells, playing a crucial role in regulating cerebellar function. However, little is known about their precise place of birth and developmental molecular machinery. Here, we describe the origin of the CF neuron lineage and the involvement of Ptf1a ( pancreatic transcription factor 1a) in CF neuron development. Ptf1a protein was found to be expressed in a discrete dorsolateral region of the embryonic caudal hindbrain neuroepithelium. Because expression of Ptf1a is not overlapping other transcription factors such as Math1 (mouse atonal homolog 1) and Neurogenin1, which are suggested to define domains within caudal hindbrain neuroepithelium (Landsberg et al., 2005), we named the neuroepithelial region the Ptf1a domain. Analysis of mice that express ␤-galactosidase from the Ptf1a locus revealed that CF neurons are derived from the Ptf1a domain. In contrast, retrograde labeling of precerebellar neurons indicated that mossy fiber neurons are not derived from Ptf1a-expressing progenitors. We could observe a detailed migratory path of CF neurons from the Ptf1a domain to the ION during embryogenesis. In Ptf1a null mutants, putative immature CF neurons produced from this domain were unable to migrate or differentiate appropriately, resulting in a failure of ION formation. Apoptotic cells were observed in the mutant hindbrain. Furthermore, the fate of some cells in the Ptf1a lineage were changed to mossy fiber neurons in Ptf1a null mutants. These findings clarify the precise origin of CF neurons and suggest that Ptf1a controls their fate, survival, differentiation, and migration during development.

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“…4C,E, arrows) (Altman and Bayer, 1987;Bourrat and Sotelo, 1988). This was confirmed by immunostaining of adjacent sections with Brn3a (Fig.…”

Section: Dynamic Movement Of Cf Neurons Produced From the Ptf1a Domainmentioning

confidence: 61%

Origin of Climbing Fiber Neurons and Their Developmental Dependence onPtf1a

Yamada¹,

Terao²,

Terashima³

et al. 2007

J. Neurosci.

106

122

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“…We found that the GC-like leading tip is the structure that generates the traction force for soma translocation, in a manner similar to the traction exerted by the leading edge on several types of nonneuronal cells, e.g., fibroblasts (Munevar et al, 2001) and keratocytes (Galbraith and Sheetz, 1999). Such a GC-traction mechanism may be used during in vivo migration of those neurons bearing a prominent GC-like structure at the distal leading process, including interneurons undergoing tangential migration in the forebrain (Polleux et al, 2002;Bellion et al, 2005), inferior olivary neurons undergoing circumferential migration from the rhombic lip around the brainstem (Bourrat and Sotelo, 1988), and granule cells undergoing subpial migration from the rhombic lip over the cerebellar cortex (Hatten, 1999). Myosin II has been identified recently as a key player in neuronal migration (Schaar and McConnell, 2005;Tsai et al, 2007;Vallee et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Leading Tip Drives Soma Translocation via Forward F-Actin Flow during Neuronal Migration

Zhang²,

Guan³

et al. 2010

J. Neurosci.

113

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Neuronal migration involves coordinated extension of the leading process and translocation of the soma, but the relative contribution of different subcellular regions, including the leading process and cell rear, in driving soma translocation remains unclear. By local manipulation of cytoskeletal components in restricted regions of cultured neurons, we examined the molecular machinery underlying the generation of traction force for soma translocation during neuronal migration. In actively migrating cerebellar granule cells in culture, a growth cone (GC)-like structure at the leading tip exhibits high dynamics, and severing the tip or disrupting its dynamics suppressed soma translocation within minutes. Soma translocation was also suppressed by local disruption of F-actin along the leading process but not at the soma, whereas disrupting microtubules along the leading process or at the soma accelerated soma translocation. Fluorescent speckle microscopy using GFP-␣-actinin showed that a forward F-actin flow along the leading process correlated with and was required for soma translocation, and such F-actin flow depended on myosin II activity. In migrating neurons, myosin II activity was high at the leading tip but low at the soma, and increasing or decreasing this front-to-rear difference accelerated or impeded soma advance. Thus, the tip of the leading process actively pulls the soma forward during neuronal migration through a myosin II-dependent forward F-actin flow along the leading process.

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“…This observation was confirmed experimentally in chick embryos (Harkmark, 1954) and by birthdating studies in rodents (Ellenberger et al, 1969;Bayer, 1978, 1985). Slice culture experiments showed that tangentially migrating inferior olivary neurons send a long leading process across the midline but that their cell body always stays ipsilateral (Bourrat and Sotelo, 1988) (Fig. 10).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons

Meglio¹,

Nguyen-Ba-Charvet²,

Tessier‐Lavigne³

et al. 2008

Journal of Neuroscience

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Precerebellar neurons of the inferior olive (IO) and lateral reticular nucleus (LRN) migrate tangentially from the rhombic lip toward the floor plate following parallel pathways. This process is thought to involve netrin-1 attraction. However, whereas the cell bodies of LRN neurons cross the midline, IO neurons are unable to do so. In many systems and species, axon guidance and cell migration at the midline are controlled by Slits and their receptor Robos. We showed previously that precerebellar axons and neurons do not cross the midline in the absence of the Robo3 receptor. To determine whether this signaling by Slits and the two other Robo receptors, Robo1 and Robo2, also regulates precerebellar neuron behavior at the floor plate, we studied the phenotype of Slit1/2 and Robo1/2/3 compound mutants. Our results showed that many IO neurons can cross the midline in absence of Slit1/2 or Robo1/2, supporting a role for midline repellents in guiding precerebellar neurons. We also show that these molecules control the development of the lamellation of the inferior olivary complex. Last, the analysis of Robo1/2/3 triple mutants suggests that Robo3 inhibits Robo1/2 repulsion in precrossing LRN axons but not in IO axons in which it has a dominant and distinct function.

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Migratory pathways and neuritic differentiation of inferior olivary neurons in the rat embryo. Axonal tracing study using the in vitro slab technique

Cited by 100 publications

References 25 publications

Origin of Climbing Fiber Neurons and Their Developmental Dependence onPtf1a

Origin of Climbing Fiber Neurons and Their Developmental Dependence onPtf1a

Leading Tip Drives Soma Translocation via Forward F-Actin Flow during Neuronal Migration

Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons

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