The Rhombic Lip And The External Granule Cell Layer Of The Cerebellum

The external granule cell layer of the cerebellum is unique among the proliferating populations of the CNS in that it is adjacent to the pial surface rather than the ventricular surface (Fig. 17). The external granule cell layer was first recognized as the source of the granule cells of the cerebellum near the end of the 19th century (Obersteiner, 1883; Schaper, 1897a, b; Ramon y

Layers Developing Cerebellum

FIGURE 17. The external granule cell layer (EGL) lies beneath the pial surface of the developing cerebellum. These stem/progenitor cells divide in the EGL and migrate through the molecular layer (Mol), past the Purkinje cells into the internal granule cell layer (IG). Drawing from Jacobson (1991), modified from Ramon y Cajal (1909-1911).

FIGURE 17. The external granule cell layer (EGL) lies beneath the pial surface of the developing cerebellum. These stem/progenitor cells divide in the EGL and migrate through the molecular layer (Mol), past the Purkinje cells into the internal granule cell layer (IG). Drawing from Jacobson (1991), modified from Ramon y Cajal (1909-1911).

Cajal, 1909-1911). The cells of the external granule cell layer originate from the rhombic lip and then migrate over the surface of the cerebellum. The rhombic lip also gives rise to neurons of the brain stem, chiefly of the inferior olivary nuclei but also of the cochlear and pontine nuclei (Harkmark, 1954; Taber-Pierce, 1973). In the human the cells migrating from the rhombic lip to the brain stem form a continuous band which was called the corpus pontobulbare by Essick (1907, 1909, 1912).

The external granule cell layer is present in every vertebrate that has been examined. It is a single layer of cells that is about 6-8 cell diameters thick. Importantly, mitotic figures are scattered throughout the external part of the layer indicating that there is no interkinetic nuclear migration. In this regard, the external granule cell layer is similar to the SVZ. The internal part of the external granule cell layer is not a proliferative zone, but instead it consists of cells that are "waiting" to migrate. The major output of the external granule cell layer is the many cells that comprise the internal granule cell, which are arguably the most numerous neurons in the brain. The life span of the external granule cell is long in comparison with the VZ that produces the Purkinje cells of the cerebellum. For example, in the mouse, the Purkinje cells are produced in a three-day period from E10 through E13 but the internal granule cells are produced over a much more extended period from late in the postnatal period through the third week after birth (Miale and Sidman, 1961). The relatively long period of neuron production in the external granule cell layer is similar in other species including humans (Zecevic and Rakic, 1976).

It is interesting to note that the two major cell classes of the cerebellum, the Purkinje cells and granule cells, are produced in two distinct proliferative zones, the VZ of the fourth ventricle and the external granule cell layer, respectively, at quite different times during development. Thus, it is clear that the final product, that is, the normal cerebellar cortex with a proper number of both types of cells, requires an elaborate regulatory system that would need to include some sort of feedback system through which the early developing cell (the Purkinje cell) could influence the production of the later developing cell (the granule cell). This interaction is hinted at by the changes in the thickness of the external granule cell layer in the reeler mutant mouse where it achieves normal thickness only in places where the Purkinje cell dendrites are normally oriented toward the pial surface (Caviness and Rakic, 1978). Recent evidence indicates that this interaction is mediated by sonic hedgehog which is released from the Purkinje cells and which then binds to the Patchedl receptor on the proliferating cells of the external granule cell layer (Corcoran and Scott, 2001). Mutations in the Patchedl receptor may be involved in the development of medulloblastoma, one of the most common brain tumors of childhood (Corcoran and Scott, 2001; Pomeroy et al., 2002).

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