Enbryology and genetics of cerebellar development

During the fourth week of development, the mesencephalic flexure and cervical flexure appear in the cranial region of the neural tube, delimiting three neural vescicles: the prosencephalon, mesencephalon and rhomboencephalon. During the fifth week, the pontine flexure forms in the roof of the rhomboencephalon, marking the division between the metencephalon and myeloencephalon, the future medulla oblongata. The dorsal part of the metencephalon (alar plate), between the mesencaphalic isthmus and the pontine flexure, will give rise to the cerebellum, whereas its ventral part (basal plate) will give rise to the pons. The alar plates, lateral to the deepening pontine fissure and the hindbrain cavity, present an intense proliferative activity with the formation of two extensions which fuse just behind the isthmus to form the cerebellar plate. During the sixth week of development, the rhombic lips appear in the posterolateral regions of this strip and after persistent proliferative activity they fuse along the median line. Median thickening of this region will give rise to the vermis, while the two lateral masses become the lateral lobes. During the seventh week, the flocculonodular lobe will form. Between the eighth and ninth weeks, the vermis expands caudally with progressive dilatation of the fourth ventricle whose Luschka and Magendie foramina are still unperforated. The cerebellar proliferation and differentiation processes are correlated to the activity of two separate germinal areas: the ependymal ventricle and the rhombic lip. From the eighth week, neuroblastic migration starts from the rhombic lip which in successive genetically controlled steps leads to the formation of the external granular layer of the cerebellar cortex. From the ventriculo-ependymal zone cells migrate to form the cerebellar nuclei destined to differentiate into Purkinje cells. The cerebellar recess starts to develop around the twelfth week with the formation of the primary fissure separating the anterior and posterior parts of the cerebellum to end with the complete formation of all cerebellar lobes at around the twenty-fourth week of development. The foliation process starts when the recess has formed and continues in the first months of life after birth. The processes of cell development and differentiation are genetically programmed and the outcome of an interaction between genetic and environmental factors. The different stages of embryonic development are thought to be controlled by sequential ordered activation of genetic clusters (homeotypic genes) which in turn encode for a series of molecules directly involved in the regulation of cell and tissue interactions. There is increasing evidence of genetic involvement in the different types of cerebellar malformation whose expression and association with other extracerebellar malformations depends on the developmental age at which the genetic change occurred.