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The Journal of Neuroscience, May 31, 2006, 26(22):6040-6051; doi:10.1523/JNEUROSCI.4815-05.2006

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Development/Plasticity/Repair
The Stop Signal Revised: Immature Cerebellar Granule Neurons in the External Germinal Layer Arrest Pontine Mossy Fiber Growth

M. Chiara Manzini,¹ M. Stanton Ward,² Qin Zhang,¹ Michael D. Lieberman,² and Carol A. Mason^1,2

¹Center for Neurobiology and Behavior, ²Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Correspondence should be addressed to Dr. Carol A. Mason, Department of Pathology, 14-509 P&S Building, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Email: cam4{at}columbia.edu

During the formation of neuronal circuits, afferent axons often enter target regions before their target cells are mature and then make temporary contacts with nonspecific targets before forming synapses on specific target cells. The regulation of these different steps of afferent-target interactions is poorly understood.

The cerebellum is a good model for addressing these aspects, because cerebellar development is well defined and identified neurons in the circuitry can be purified and combined in vitro. Previous reports from our laboratory showed that cultured granule neurons specifically arrest the extension of their pontine mossy fiber afferents, leading us to propose that granule cells arrested growth of their afferents as a prelude to synaptogenesis. However, we knew little about the differentiation state of the cultured granule cells that mediate afferent arrest.

In this study, we better define the purified granule cell fraction by marker expression and morphology, and demonstrate that only freshly plated granule cells in the precursor and premigratory state arrest mossy fiber outgrowth. Mature granule cells, in contrast, support extension, defasciculation, and synapse formation, as in vivo. In addition, axonal tracing in vivo during the first postnatal week indicates that immature mossy fibers extend into the Purkinje cell layer but never into the external germinal layer (EGL), where precursors of granule cell targets reside. We found that the stop-growing signals are dependent on heparin-binding factors, and we propose that such signals in the EGL restrict the extension of mossy fiber afferents and prevent invasion of proliferative regions.

Key words: development; cerebellum; pons; granule cell; axon outgrowth; synaptogenesis

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Received Nov. 9, 2005; revised April 21, 2006; accepted April 26, 2006.

Correspondence should be addressed to Dr. Carol A. Mason, Department of Pathology, 14-509 P&S Building, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Email: cam4{at}columbia.edu

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Growth Cone Stop Signals: Inviting to Stay or Sending Away?

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