Development and developmental disorders of the human cerebellum

J Neurol (2003) 250 : 1025–1036 DOI 10.1007/s00415-003-0199-9 H. J. ten Donkelaar M. Lammens P. Wesseling H. O. M. Thijssen W. O. Renier Received: 21 February 2003 Received in revised form: 26 June 2003 Accepted: 1 July 2003 H. J. ten Donkelaar (쾷) · M. Lammens · W. O. Renier 321 Dept. of Neurology University Medical Centre Nijmegen P. O. Box 9101 6500 HB Nijmegen, The Netherlands Tel.: +31-24/3613459 Fax: +31-24/3541122 E-Mail: [email protected] M. Lammens · P. Wesseling Dept. of Pathology University Medical Centre Nijmegen Nijmegen, The Netherlands H. O. M. Thijssen Dept. of Radiology University Medical Centre Nijmegen Nijmegen, The Netherlands W. O. Renier Dept. of Pediatric Neurology University Medical Centre Nijmegen Nijmegen, The Netherlands REVIEW Development and developmental disorders of the human cerebellum ■ Abstract The human cerebellum develops over a long time, extending from the early embryonic period until the first postnatal years. This protracted development makes the cerebellum vulnerable to a broad spectrum of developmental disorders. The development of the cerebellum occurs in four basic steps: 1) characterization of the cerebellar territory at the midbrain-hindbrain boundary; 2) formation of two compartments for cell proliferation: first, the Purkinje cells and the deep cerebellar nuclei arise from the ventricular zone of the metencephalic alar plate; second, granule cell precursors are formed from a second compartment of proliferation, i. e. the upper rhombic lip; 3) inward migration of the granule cells: granule precursor cells form the external granular layer, from which (and continuing into the first postnatal year), gran- Introduction ■ Key words cerebellum · rhombic lip · development · congenital malformations · Dandy-Walker malformation · pontocerebellar hypoplasias. This protracted development makes the cerebellum vulnerable to a broad spectrum of developmental disorders, ranging from the Dandy-Walker and related malformations to medulloblastoma, a neoplasia of granule precursor cells [23, 63, 75, 76]. Ultrasonography and magnetic resonance imaging (MRI) make it possible to detect cerebellar malformations at an early stage of development [6, 45]. In mice, the molecular mechanisms of cerebellar development are rapidly being unraveled [27, 34, 60, 65, 93, 97]. Similar mechanisms are likely to be involved in the development of the human cerebellum. We will review the morphogenesis and histogenesis of the JON 1199 The cerebellum is one of the most studied parts of the brain. Its three-layered cortex and well-defined afferent and efferent fiber connections make the cerebellum a favorite field for research on development and fiber connections of the central nervous system [92]. The cerebellum plays a role not only in motor control but also in motor learning and cognition [57]. The cerebellum develops over a long period of time, extending from the early embryonic period until the first postnatal years. ule cells migrate inwards to their definite position in the internal granular layer, and 4) formation of cerebellar circuitry and further differentiation. The precerebellar nuclei, i. e. the pontine nuclei and the inferior olive, arise from the lower rhombic lip. Developmental disorders of the cerebellum are often accompanied by malformations of the precerebellar nuclei. In this review the development of the cerebellum and some of its more frequent developmental disorders, such as the Dandy-Walker and related midline malformations, and the pontocerebellar hypoplasias, are discussed. 1026 cerebellum, the mechanisms involved, and its more frequent developmental disorders, the latter illustrated with MRI data and autopsy cases. Morphogenesis of the cerebellum The cerebellum arises bilaterally from the alar layers of the first rhombomere [67]. The two cerebellar primordia are generally considered to unite dorsally to form the vermis, early in the fetal period. Sidman and Rakic [82], however, advocated Hochstetter’s [37] view that such a fusion does not take place, and suggested one cerebellar primordium. This tuberculum cerebelli consists of a band of tissue in the dorsolateral part of the alar plate that straddles the midline in the shape of an inverted V (Fig. 1a). The arms of the V direct caudally as well as laterally, and thicken enormously, accounting for most of the early growth of the cerebellum. The rostral, midline part of the V, however, remains small and relatively inconspicuous. The further morphogenesis of the cerebellum can be summarized as follows: 1) the caudally and laterally directed limbs of the tuberculum cerebelli thicken rapidly during the sixth postovulatory week and bulge downwards into the fourth ventricle, on each side giving rise to the internal cerebellar bulge or innerer Kleinhirnwulst of Hochstetter which together form the corpus cerebelli (Fig. 1b); 2) during the seventh week of development, the rapidly growing cerebellum bulges outwards as the external cerebellar bulges (Hochstetter’s äusserer Kleinhirnwulst) which represent the flocculi, that are delineated by the posterolateral fissures; 3) during the third month of development, i. e. in the early fetal period, growth of the midline component accelerates Fig. 1 Early development of the human cerebellum: a, at approximately 4 weeks of development (after Jakob [41]); b, at the end of the embryonic period (after Hochstetter [37]), and c, at 13 weeks of development (after Sidman and Rakic [82]). The V-shaped tuberculum cerebelli is shown in gray, and the upper and lower rhombic lips by vertical and horizontal hatching, respectively. In c, open arrows show the migration paths from the rhombic lips. Abbreviations: cbi internal cerebellar bulge; ci colliculus inferior; Cpb corpus pontobulbare; cs colliculus superior; is isthmus; mes mesencephalon; nV trigeminal nerve; tbac tuberculum acusticum; tbcb tuberculum cerebelli; tbpo tuberculum ponto-olivare; 2, 4, 6: rhombomeres and begins to fill the gap between the limbs of the V, thereby forming the vermis, and 4) by the 12th to 13th weeks of development, outward, lateral and rostral growth processes have reshaped the cerebellum to a transversely oriented bar of tissue overriding the fourth ventricle (Fig. 1c). At the 12th week of development, fissures begin to form transversely to the longitudinal axis of the brain, first on the vermis and then spreading laterally into the hemispheres (Fig. 2). The first fissure to appear, i. e. the fissura posterolateralis, separates the main body of the cerebellum from the flocculonodular lobe. This caudal lobe is also known as the vestibulocerebellum or archicerebellum. The corpus cerebelli consists of the spinocerebellum (or paleocerebellum) medially, and the pontocerebellum (or neocerebellum) laterally.The fissura prima divides the cerebellar hemispheres into anterior and posterior lobes. Four basic steps in the development of the cerebellum The development of the cerebellum occurs in four basic steps [4, 27, 33, 34, 60, 93]: 1) characterization of the cerebellar territory in the hindbrain; 2) formation of two compartments of cell proliferation, giving rise to the Purkinje cells and the granule cells, 3) inward migration of the granule cells, and 4) formation of cerebellar circuitry and further differentiation. A large number of genes is involved in the formation of the cerebellum [27, 33, 34, 65, 93]. More than 20 spontaneous mice mutations are known that affect the cerebellum [33, 62].