ReviewThe rhombic lip and early cerebellar development
Section snippets
Introduction: a brief history of the rhombic lip
The embryonic rhombic lip [1] is a specialised germinative epithelium that arises relatively late in development at the interface between the neural tube and the roofplate of the fourth ventricle (Fig. 1a). Its derivatives are specific to the cerebellar and precerebellar systems and, in particular, it has long been hypothesised as the initial origin of cerebellar granule cells [2], by far the most numerous neuron in the central nervous system (CNS). Beyond their functional significance, defects
Regional origins of the cerebellar rhombic lip in development
The midbrain/hindbrain region has been the subject of numerous fate-mapping studies investigating the regional origins of the cerebellum and its constituent cell groups. Chimaeras are constructed by orthotopic transplant of (usually) quail tissue into chick embryos in ovo (quail cells can then be identified much later in the resulting chimaera). Investigators use the morphological constrictions that subdivide the early embryonic neural tube into vesicles as grafting landmarks in the
Induction of the rhombic lip
The positioning of the rhombic lip at the interface between roofplate and neural tube, and the similarity of its marker profile to that of otherwise dorsal cell types within the CNS (e.g. mouse Atonal homologue 1, MATH1 [22]), suggest that its identity is conferred by well-characterised dorsoventral cues within the neural tube. However, rhombic lip territory is not specified early in embryonic development. Rather, its induction is the result of an ongoing interaction between neural tube and
Migration of cerebellar rhombic lip derivatives
Rhombic lip derivatives are characterised by their distinctive, glia-independent circumferential navigation from dorsal to ventral neural tube. Both migrating granule precursors [10] and pontine neurons [35] exhibit a characteristic unipolar morphology where a single leading process appears to guide migration (Fig. 3c). A number of candidate guidance molecules are expressed at the rhombic lip (Table 1), some of which have, as yet, no defined role in tangential migration (e.g. erbB4 [36, [37],
Conclusions
The cerebellar rhombic lip emerges through the precise interaction of anteroposterior and dorsoventral patterning processes. It is induced in r1, a region flanked by domains of Otx and Hox gene expression, through local BMP signalling from the roofplate of the fourth ventricle. The cerebellar and hindbrain rhombic lip form a continuous proliferative epithelium, characterised by a number of spatio-temporally overlapping molecular markers and containing one or more distinct precursor pools. For
Update
A retroviral fate-mapping study of the cerebellum reveals that a single precursor can generate not only granule cells but also a variety of ventral neuronal sub-types including cells in the locus coeruleus [57]. The authors favour the interpretation that the latter ventrally located neurons are derived directly from precursors within the EGL. However, retroviral labelling was performed at early embryonic stages, long before the formation of the rhombic lip and hence prior to the induction of
Acknowledgements
With thanks to Dr Anna Myat for critical reading of the manuscript and Moheb Costandi for help with additional research. RJT Wingate is a Wellcome Career Development Fellow and a member of the MRC Centre for Developmental Neurobiology.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
of special interest
of outstanding interest
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