Functional Krox20 binding sites have been identified in enhancers of murine Hoxa2, Hoxb2, and Hoxb3.114,124,125,128,161 The Krox20-dependent enhancers of Hoxa2 and Hoxb2 drive expression of these genes in r3 and r5125,128 and are conserved in both chicken and pufferfish.123,124 Regulation of Hoxb3 expression in r5 requires both Krox20 and KRML1.114 Krox20 binding sites have also been identified in the promoter regions of Hoxa4,162 and human HOXA7 andHOXA9.163,164 However, none of these genes are expressed in r3 and r5. These Krox20 bindingsites may regulate expression of these genes in other tissues where Krox20 is expressed such as inthe myelinating Schwann cells, chondrocytes, or osteoblasts. Krox20 has also been found to regulate the segmental expression of EphA4 in r3 and r5 of the hindbrain.165
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The cerebellum is a large, complex brain structure that mediates essential functions for movement, balance, cognition, and language (Ito, 2005). Development of the cerebellum critically depends on Reelin signaling. Complete deficiency of Reelin causes a severe cerebellar malformation, with extensive cellular disorganization and hypoplasia. Identical cerebellar defects are observed in mice lacking downstream components of the Reelin signaling pathway, including Reelin receptors VLDLR and ApoER2, adapter protein Dab1, or kinases Fyn and Src. The brain malformation results in ataxia and loss of balance, manifesting as a reeling gait in mice (hence the name Reelin) and multiple neurological problems in humans. More subtle abnormalities of Reelin signaling may underlie important neurobehavioral disorders in humans. In particular, some studies have linked RELN gene polymorphisms and reduced Reelin expression to autism. Since cerebellar defects are frequently observed in autistic brains, an attractive hypothesis is that Reelin signaling abnormalities may cause autism by perturbing cerebellar development or plasticity. 2ff7e9595c
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