Review
The rhombic lip and early cerebellar development

https://doi.org/10.1016/S0959-4388(00)00177-XGet rights and content

Abstract

Recent studies have transformed our understanding of the embryonic rhombic lip by revealing the inductive cues, regional origins and guidance molecules that pattern the development of this important structure and its derivatives. In the cerebellum, a precise combination of anteroposterior and dorsalising cues induces a stream of migratory progenitors that give rise to the external granule cell layer, while more caudally, Netrin orchestrates the migration of hindbrain rhombic lip derivatives to form the precerebellar nuclei. The rhombic lip is thus emerging as a spatiotemporally distinct epithelium whose late appearance in both development and evolution is instrumental in generating a complex, functionally related but spatially distributed neural system.

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 [10radical dotradical dot] and pontine neurons [35radical dot] 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:

radical dotof special interest

radical dotradical dotof outstanding interest

References (60)

  • JG Culotti et al.

    DCC and netrins

    Curr Opin Cell Biol

    (1998)
  • A Augsburger et al.

    BMPs as mediators of roof plate repulsion of commissural neurons

    Neuron

    (1999)
  • AL Joyner

    Engrailed, Wnt and Pax genes regulate midbrain–hindbrain development

    Trends Genet

    (1996)
  • LZ Holland et al.

    Chordate origins of the vertebrate central nervous system

    Curr Opin Neurobiol

    (1999)
  • R Nieuwenhuys

    Comparative anatomy of the cerebellum

  • A Eichmann et al.

    The expression pattern of the mafB/kr gene in birds and mice reveals that the kreisler phenotype does not represent a null mutant

    Mech Dev

    (1997)
  • K Keino-Masu et al.

    Deleted in Colorectal Cancer (DCC) encodes a netrin receptor

    Cell

    (1996)
  • S Guo et al.

    Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a

    Neuron

    (1999)
  • W His

    Die entwickelung des menschlichen rautenhirns vom ende des ersten bis zum beginn des dritten monats. I. Verlängertes Mark

    Abh Kön Sächs Ges d Wiss Mat Phys Kl

    (1890)
  • A Schaper

    Die frühsten differenzierungsvorgänge im centralnervensystem

    Arch Entw mech Org

    (1897)
  • KJ Millen et al.

    Neurogenetics of the cerebellar system

    J Child Neurol

    (1999)
  • W Harkmark

    The rhombic lip and its derivatives in relation to the theory of neurobiotaxis

  • W Harkmark

    Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons. A morphological and experimental investigation of chick embryos

    J Comp Neurol

    (1954)
  • J Altman et al.

    Development of the precerebellar nuclei in the rat: II. The intramural olivary migratory stream and the neurogenetic organization of the inferior olive

    J Comp Neurol

    (1987)
  • J Altman et al.

    Development of the precerebellar nuclei in the rat: III. The posterior precerebellar extramural migratory stream and the lateral reticular and external cuneate nuclei

    J Comp Neurol

    (1987)
  • J Altman et al.

    Development of the precerebellar nuclei in the rat: IV. The anterior precerebellar extramural migratory stream and the nucleus reticularis tegmenti pontis and the basal pontine gray

    J Comp Neurol

    (1987)
  • RJ Wingate et al.

    The role of the rhombic lip in avian cerebellum development

    Development

    (1999)
  • ME Hatten et al.

    Mechanisms of neural patterning and specification in the developing cerebellum

    Annu Rev Neurosci

    (1995)
  • ME Hallonet et al.

    A new approach to the development of the cerebellum provided by the quail–chick marker system

    Development

    (1990)
  • S Millet et al.

    The caudal limit of Otx2 gene expression as a marker of the midbrain/hindbrain boundary: a study using in situ hybridisation and chick/quail homotopic grafts

    Development

    (1996)
  • Cited by (0)

    View full text