Pattern Deformities and Cell Loss inEngrailed-2Mutant Mice Suggest Two Separate Patterning Events during Cerebellar Development

Abstract

Null alleles of the mouse Engrailed-2 gene, a molecular homolog of the fly gene engrailed, have demonstrable effects on the anteroposterior (A/P) patterning of cerebellum as reflected in the disruption of the normal process of foliation of the cerebellar cortex and the alteration of transgene expression boundaries in the adult. Engrailed-2 also affects the transient mediolateral (M/L) pattern of En-1 and Wnt-7b expression seen in late embryogenesis. We have examined three markers of cerebellar compartmentation in En-2 mutant mice: the Zebrin II and Ppath monoclonal antibodies and the transgene L7lacZ. In En-2 mutants, the normal temporal pattern of expression is preserved for all three markers, although the size and spatial location of various bands differ from those of the wild type. Unlike the foliation abnormalities, the M/L pattern disturbances we have found occur in nearly all cerebellar regions. Cell counts reveal that all major cell types of the olivocerebellar circuit are reduced by 30-40%. We propose that these results are best explained by a model in which the Engrailed-2 gene is involved in the early specification of the cerebellar field including the number of progenitors. Because each of these progenitors gives rise to a clone of defined size, Engrailed-2 helps specify adult cell number. We further postulate that the configuration of the seven Zebrin bands as well as the shapes and locations of the cerebellar lobules are set up by a second patterning event that occurs after neurogenesis is complete.

The mouse Engrailed genes: A window into autism

“…The folial abnormalities are similar to the distortions seen in autistic individuals as reported by Courchesne and colleagues [23]. There is also a significant decrease in the number of Purkinje, granule, deep nuclear and inferior olive cells in the En2 mutant [40]. This again is reminiscent of previously reported neuroanatomical abnormalities observed in autistic individuals [10,11].…”

“…Other markers of cerebellar compartmentation are also disrupted in both the vermis and hemispheres of the En2 hd null mutant. These include Zebrin II, Ppath and the expression of a L7lacZ fusion gene [40].…”

Advances in behavioral genetics: mouse models of autism

“…34,300 Changes in brain morphology include a smaller cerebellum with aberrant foliation and reduced numbers of Purkinje and granule neurons. 301,302 The cerebellar neuropathology emerges during embryonic development of the mutant mice. 303 In a recent report and overview, Kuemerle et al 299 note that the En2-null mice also evidence an anterior shift in the position of amygdalar nuclei, which may reflect a similar shift observed in a rat model for prenatal exposure to valproic acid.…”

The expression pattern of nuclear receptors during cerebellar development

“…By the end of the third postnatal week (P21) in the mouse, the EGL ceases to exist, and the cerebellum achieves its mature laminated structure consisting of three layers: the molecular layer (ML), the Purkinje cell layer (PCL), and the granular layer (GL) (Voogd and Glickstein, 1998). Furthermore, along the anterior-posterior axis including the ten lobules, the vermis is also divided into the anterior (lobule I to V/VI) and posterior compartment (lobule V/VI to X) (Kuemerle et al, 1997). The existence of this morphological boundary for the anterior and posterior cerebellum is supported by observations of structural abnormalities that are restricted primarily to the anterior or posterior cerebellum lobules in loss of function assays, such as that observed for the Engrailed-2 and BETA2/NeuroD1 genes (Ackerman et al, 1997;Kuemerle et al, 1997;Cho and Tsai, 2006).…”

“…Furthermore, along the anterior-posterior axis including the ten lobules, the vermis is also divided into the anterior (lobule I to V/VI) and posterior compartment (lobule V/VI to X) (Kuemerle et al, 1997). The existence of this morphological boundary for the anterior and posterior cerebellum is supported by observations of structural abnormalities that are restricted primarily to the anterior or posterior cerebellum lobules in loss of function assays, such as that observed for the Engrailed-2 and BETA2/NeuroD1 genes (Ackerman et al, 1997;Kuemerle et al, 1997;Cho and Tsai, 2006). In conclusion, the profound morphological transformations that occur during development make the cerebellum an extremely useful organ for studying neurogenesis.…”