A role for midbrain arcs in nucleogenesis

Development, Dec 2002

Seema Agarwala, Clifton W. Ragsdale

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A role for midbrain arcs in nucleogenesis

Seema Agarwala 0 Clifton W. Ragsdale 0 0 Department of Neurobiology, Pharmacology and Physiology, The University of Chicago , Chicago, IL 60637, USA - Nuclei are fundamental units of vertebrate brain organization, but the mechanisms by which they are generated in development remain unclear. One possibility is that the early patterning of brain tissue into reiterated territories such as neuromeres and columns serves to allocate neurons to distinct nuclear fates. We tested this possibility in chick embryonic ventral midbrain, where a periodic pattern of molecularly distinct stripes (midbrain arcs) precedes the appearance of midbrain nuclei. We found that midbrain arc patterning has a direct relationship to the formation of nuclei. Both differential homeobox gene expression and diagnostic axon tracing studies established that the most medial arc contains primordia for two major midbrain nuclei: the oculomotor complex and the red nucleus. We tested the relationship of the medial arc to oculomotor complex and red nucleus In the adult brain, many neurons are organized into welldelineated clusters of characteristic shape and size. The role of these clusters, known as nuclei, is to organize neuronal circuitry. Thus, for a brain neuron, the projections of its axons, the neurotransmitters it employs and the local and longdistance inputs it receives, are governed by its nuclear assignment. Despite major recent insights into the early patterning events of the neural tube (Jessell and Lumsden, 1997), very little is known about the cellular and molecular patterning mechanisms that generate discrete brain nuclei of appropriate size, location and cell-type composition. The ventral midbrain provides an elegant model system for addressing the mechanisms of brain nucleogenesis. The adult midbrain tegmentum exhibits a complex structural architecture featuring spherical, ovate and plate-shaped nuclei. During embryogenesis, this nuclear organization is preceded by a more regular organization into a reiterated series of arcuate territories called midbrain arcs (Agarwala et al., 2001; Sanders et al., 2002). Arcs are known to be molecularly distinct, differing, for example, in their expression of homeobox genes (Agarwala et al., 2001). Whether the arcs simply reflect a mechanism for regulating the numbers of distinct midbrain cell-types or serve a more specific role in allocating neurons to particular nuclear fates is unknown. The possibility that developmental periodicities might development by perturbing arc pattern formation in Sonic Hedgehog and FGF8 misexpression experiments. We found that Sonic Hedgehog manipulations that induce ectopic arcs or expand the normal arc pattern elicit precisely parallel inductions or expansions of the red nucleus and oculomotor complex primordia. We further found that FGF8 manipulations that push the medial arc rostrally coordinately move both the red nucleus and oculomotor complex anlagen. Taken together, these findings suggest that arcs represent a patterning mechanism by which midbrain progenitor cells are allocated to specific nuclear fates. provide a patterning substrate for nucleogenesis has been addressed in connectional and fate-mapping studies of hindbrain rhombomeres. The striking finding is that most brainstem nuclei are generated from serially adjoining sets of rhombomeres with few nuclei developing from single rhombomeres (Cramer et al., 2000; Diaz et al., 1998; Lumsden and Keynes, 1989; Marin and Puelles, 1995). Thus, the extent to which anteroposterior periodicities are crucial to hindbrain nuclear specification remains uncertain (Wingate and Lumsden, 1996). Indeed, the generation of hindbrain nuclei, many of which form longitudinal columns, may be more tightly regulated in the mediolateral dimension (Clarke et al., 1998; Marin and Puelles, 1995). This observation is of particular interest because midbrain arcs, unlike hindbrain rhombomeres, are arrayed along the mediolateral axis parallel to the ventral midline. In these studies, we explored the relationship between arc pattern formation and the generation of midbrain nuclei by focusing on the most medial arc as a prototypical arc. Using diagnostic connectional and molecular criteria we identified the anlagen for at least two midbrain nuclei within the medial arc: the oculomotor complex (OMC) and the red nucleus (RN). Both of these nuclei are part of the motor system, but their functions and connections are so dissimilar that a shared origin in the same arc was unexpected. The OMC contains motoneurons that control eye movements and the parasympathetic regulation of accommodation and pupil contraction (Evinger, 1988). The RN, by contrast, contains no motoneurons but is a cerebellar-related nucleus mediating motor cortex and cerebellar outflow to spinal cord in the control of limb movements (Holstege and Tan, 1988; Keifer and Houk, 1994; ten Donkelaar, 1988). The two medial arc pronuclei are also molecularly distinct, differing (...truncated)


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Seema Agarwala, Clifton W. Ragsdale. A role for midbrain arcs in nucleogenesis, Development, 2002, pp. 5779-5788, 129/24, DOI: 10.1242/dev.00179