The cerebellar rhombic lip is a germinal zone that is located between the fourth ventricle and the roof plate, and has traditionally been thought to generate only precursor cells that give rise to granule cells, the most common type of cerebellar neuron. Two fate-mapping studies, published in Neuron, challenge this view of cerebellar and pre-cerebellar development, and, for the first time, characterize several distinct cell populations that emerge from the cerebellar rhombic lip. Importantly, they reveal that the basic helix–loop–helix transcription factor Math1 is pivotal for establishing this neuronal diversity, and that timing is a crucial determinant for cell type.
Machold and Fishell used an innovative molecular mapping technique (developed by their colleagues in the Joyner laboratory) in embryonic mice to specifically label and track over time Math1-positive neural progenitor cells that originated in the cerebellar rhombic lip. Unexpectedly, they found that early in embryogenesis (before embryonic day (E)12.5) Math1-positive cells generated not only deep cerebellar nuclei, but also specific migratory non-granule cell types of the rostral hindbrain, including cholinergic neurons of the mesopontine tegmental nuclei, all of which contribute to the cerebellar/vestibular/auditory network. Math1 seems to be only transiently expressed in these cells, but is crucial for generating the diversity of neuronal types, as absence of this transcription factor prevented their development.
After E12.5, however, Math1 was persistently expressed in precursor cells, which principally developed into granule cells. Of these, the most distal extracerebellar nuclei were the first to emerge, whereas those that populate more posterior regions, and therefore have a shorter migration distance, arose later in development.
In a contrasting approach, Wang and colleagues tracked derivatives of the rhombic lip by monitoring Math1-driven β-galactosidase expression. They too reported diverse Math1-expressing cell types in the cerebellum, pons and isthmus that originated in the rostral rhombic lip, and identified some further groups of migratory cells, including cochlear granule cells and non-granule ventral cochlear neurons, which emerged from a more caudal portion of the rhombic lip. Intriguingly, cerebellar and cochlear neurons that arose from the adjacent ventromedial neuroepithelium lacked Math1.
On the basis of these patterns of Math1 expression, Wang and co-workers proposed that Math1 defines the spatial limits of the rhombic lip, the anatomical boundaries of which have, so far, been difficult to distinguish from the ventricular epithelium.
These results indicate that a specific transcription factor influences the integration of diverse cell types into common pathways that are involved in proprioception, balance and audition. Moreover, they reveal the importance of temporal dynamics, in addition to spatial origin, in the specification of cell types in the hindbrain. It is hoped that future work will unravel the molecular mechanisms that coordinate this precise temporal regulation in the developing neural tube.
ORIGINAL RESEARCH PAPERS
Machold, R. & Fishell, G. Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48, 17–24 (2005)
Wang, V. Y., Rose, M. F. & Zoghbi, H. Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48, 31–43 (2005)
Zervas, M. et al. Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1. Neuron 43, 345–357 (2004)
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Rowan, A. The mystery of Maths. Nat Rev Neurosci 6, 916 (2005). https://doi.org/10.1038/nrn1813