Illegal Immigrations
Authors: Pasko Rakic
Journal: Neuron (2000)

In most cases, the constituent neurons of most structures in the mammalian central nervous system (CNS) are generated within the embryonic proliferative zones of the same brain subdivision in which they will ultimately reside in the adult organism (8Rakic P Experientia. 1990; 46: 170-176Crossref Scopus (555) Google Scholar), and the interdivisional borders seem to be well respected (11Rubenstein J.L.R. Martinez S. Shimamura K. Puelles L Science. 1994; 266: 578-580Crossref PubMed Scopus (421) Google Scholar). There are some notable exceptions where newborn neurons do not obey this law and trespass to foreign territories. The oldest and best-known example of this behavior is the migration of late-generating neurons from the rhombic lip of the dorsal rombencephalon to the complex of gray nuclei of the pons (PGN) and the inferior olive of the medulla (2Essick C.R Am. J. Anat. 1912; 13: 25-45Crossref Scopus (99) Google Scholar). More recently, direct evidence for this hypothesis has come from quail chick chimera fate mapping experiments (13Wingate R.J. Hatten M.E Development. 1999; 126: 4395-4404PubMed Google Scholar). These brainstem structures are also known as precerebellar nuclei because they provide major cerebellar afferent systems—the mossy and climbing fibers—to the granule and Purkinje cells, respectively (Figure 1). Another, atypical example of transdivisional crossing occurs during late gestation in the human brain where there is massive migration of neurons from the ganglionic eminence, the proliferative center of the telecephalon, to the association nuclei of the thalamus in the diencephalon (9Rakic P. Sidman R.L Z. Anat. Entwickl.-Gesch. 1969; 129: 53-82Crossref PubMed Scopus (95) Google Scholar). In contrast, there are other well-known cases of long-distance migration where cells do not break any immigration laws. For instance, neurons generated in the subventricular zone of the telecephalon also migrate long distances to reach their final destination in the olfactory bulb, but, in this case, these cells stay within the jurisdiction of the telencephalon (e.g., 5Luskin M.B Neuron. 1993; 11: 173-189Abstract Full Text PDF PubMed Scopus (1565) Google Scholar, 4Lois C. Alvarez-Buylla A Science. 1994; 264: 1145-1148Crossref PubMed Scopus (1884) Google Scholar). Thus, there are only a few exceptions to the general rule that the individual and species-specific size of a given brain subdivision depends on the supply of neurons produced within its own germinal territory. In the current issue of Neuron, 10Rodriguez C.I. Dymecki S.M Neuron. 2000; 27 (this issue,): 475-486Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar have proven experimentally that neurons of the precerebellar nuclei indeed derive from the dorsal rhombic lip (DRL). In addition, they provide the first evidence that the brain nuclei that project to different target neurons in the cerebellar cortex originate from distinct precursor populations in the rhombic lip. This finding is somewhat surprising, since the DRL is also known to give rise to the external granular layer that eventually produces the distinctive granule cells of the cerebellum (Figure 1). To obtain the birth certificates of these migrant neurons was not an easy task. The authors used a site-specific FLP/FRT recombination-based fate mapping approach, which transforms the transient expression of an FLP recombinase under the cell- or tissue-specific promoter, into a permanent label. In particular, Rodriguez and Dymecki's study shows that Wnt1 expression demarcates common progenitors for PGN cells that will form mossy fibers already in the DRL, before onset of their migration, while Wnt expression is absent in the progenitors of neurons that will form climbing fibers. The members of the large Wnt family are secreted signaling molecules associated with the extracellular matrix and have been shown to function in various aspects of neuronal development, including fate determination, polarity, adhesion, migration, and synapse formation (3Hall A. Lucas F. Salinas P Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar, 7Patapoutian A. Reichardt L.F Curr Opin Neurobiol. 2000; 10: 392-399Crossref PubMed Scopus (259) Google Scholar). Although the precise role of Wnt signaling in directing neuronal migration across the interdivisional border is not known, to my knowledge, this is the first evidence that the brain stem mossy fiber system can be distinguished from the climbing fiber system before connections with their respected targets are established. However, a possibility that other members of the large Wnt family or other unrelated molecules might also be expressed in and serve as early markers for the progenitors of the climbing fiber system cannot be excluded. It also seems possible that the activity of different members of the Wnt family could be crucial in establishing different modes of migration and patterns of connectivity for various other cerebellar populations. The approach used in this study provides a useful paradigm for how the development of other CNS structures could be analyzed with modern methodology. Finally, Rodriguez and Dymecki's report provides another instructive example that postmitotic neurons already have their travelling itinerary, final address, as well as the hint of their phenotypic determination at the time of their birth in the proliferative zone well before arriving at their place of residence. Similar early specification has been observed in the ventricular zone of the telecephalon. Here, neurons that are ultimately destined for different cortical layers and that eventually form different sets of connections already have information of their proper laminar addresses at the site of their birth (6McConnell S.K. Kazanowski C.J Science. 1991; 254: 282-285Crossref PubMed Scopus (607) Google Scholar). Among the problems that still need to be solved is how postmitotic neurons find their way across the interdivisional border, through the forbidden terrain already packed with the previously generated, often synaptically interconnected neuropile. This problem can be fully appreciated only when taking into consideration the intricate anatomical and developmental relationships in this region (Figure 1). Thus, unlike the sensorimotor nuclei (SMN) of the brain stem that have been generated earlier and that have already completed their radial migration from the local ventricular zone (12Sidman R.L. Rakic P Brain Res. 1973; 62: 1-35Crossref PubMed Scopus (950) Google Scholar), the PGN cells of the DRL migrate tangentially, parallel to the pontine surface. As indicated in Figure 1, PGN neurons extend their elongated leading process below the pia, closely apposed to the axonal tracts that run parallel to the brain surface. While on course, these neurons appear to ignore numerous radial glial fibers that run perpendicular to their trajectory, suggesting that a homotypic-neurophilic migration (same adhesion molecules on the adjacent neuronal surfaces) may be involved (8Rakic P Experientia. 1990; 46: 170-176Crossref Scopus (555) Google Scholar). It was recently shown that the secreted chemoattractant netrin-1, in association with its receptor DCC, attracts the leading process toward the midline (14Yee K.T. Simon H.H. Tessier-Lavigne M. O'Leary D.M.D Neuron. 1999; 24: 607-622Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). However, an important point that was not considered in most of the previous papers is that a majority of these neurons migrating across the midline ultimately settle into the PGN on the opposite side and eventually form the synapses with the granule cells of the contralateral cerebellar hemisphere (Figure 1). In other words, while pontine neurons are propelled away from their birth site on the ipsilateral side, they are attracted to the corresponding site on the contralateral side. This raises the question of how the apparently distinct attractive and repulsive effects of the contralateral and ipsilateral hemispheres are achieved. One likely possibility is that these migrating neurons change their response properties as they cross the midline. It would also be important to create an FRT-containing indicator strain with a cytoplasmic label such as β-LacZ or GFP to be able to follow the trajectory of the individual axons from the cell soma to their terminals during development. It is well established that during phylogenesis, individual brain structures with major anatomical and functional links evolve in a coordinated way (1Barton A.R. Harvey P.H Nature. 2000; 405: 1055-1058Crossref PubMed Scopus (517) Google Scholar). Like ancestors who come from the same homeland and then drift apart, only to reconnect later in life, neurons born in the same region may ultimately become permanent residents in different brain subdivisions and eventually develop specific synaptic contacts with one another. However, the developmental mechanisms for orchestrating cell production and allocation are not well understood. Since precerebellar pontine nuclei serve as a relay of information within the cortico-ponto-cerebellar system, an additional complement of neurons must be imported to the pons to accommodate input from the expanding neocortex at late stages of development when the rhombic lip is the only proliferation center that is still active in that region and still reachable by diffusible factors. This again exposes the significance of lineage relationships that can be observed but are still not fully understood.