The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that regulate target gene transcription. We report the molecular cloning and characterization of a novel human cDNA encoding TRAM-1, a thyroid hormone receptor activator molecule, a ϳ160-kDa protein homologous with SRC-1/TIF2, by far-Western-based expression screening. TRAM-1 binds to thyroid hormone receptor (TR) and other NRs in a liganddependent manner and enhances ligand-induced transcriptional activity of TR. The AF-2 region in NRs has been thought to play a critical role in mediating ligand-dependent transactivation by the interaction with coactivators. Surprisingly, TRAM-1 retains strong ligand-dependent interaction with an AF-2 mutant of TR (E457A), while SRC-1 fails to interact with this mutant. Furthermore, we identified a critical TRAM-1 binding site in rat TR␤1 outside of AF-2, as TRAM-1 shows weak ligand-dependent interaction with a helix 3 ligand binding domain TR mutant (K288A), compared with SRC-1. These results suggest that TRAM-1 is a coactivator that may exhibit its activity by interacting with subdomains of NRs other than the AF-2 region, in contrast to SRC-1/TIF2.The nuclear hormone receptors (NRs) 1 regulate target gene transcription in response to various ligands including steroids, thyroid hormone (T 3 ), retinoids, and vitamin D. The liganded NRs bind to their cognate response elements, located in the promoter regions of target genes, and stimulate transcription by the interaction with coactivators. Functional analysis of NRs has shown that there are two major activation domains.The N-terminal domain (AF-1) contains a ligand-independent activation function, whereas the extreme C-terminal region of the ligand binding domain (AF-2) exhibits ligand-dependent transactivation (1). The AF-2 region is conserved among NRs, and deletion or point mutations in this region impair transcriptional activation without changing ligand and DNA binding affinities (2-4). Recent x-ray crystallographic studies of the ligand binding domain of NRs revealed that the ligand induces a major conformational change in the AF-2 region (5-7), suggesting that this region may play a critical role in mediating transactivation by a ligand-dependent interaction with coactivators. Several putative coactivators of NRs have been identified, using either far-Western or yeast two-hybrid techniques, including SRC-1, RIP140, TIF1, TIF2, and CREB binding protein (CBP)/p300 (8 -14). As expected, these proteins fail to interact with AF-2 mutants of .Using bacterially expressed thyroid hormone receptor (TR) as a probe, a cDNA expression library was screened, and a novel cDNA encoding TRAM-1, a putative thyroid hormone receptor activator molecule, was isolated. TRAM-1 belongs to a nuclear receptor coactivator (NCoA) gene family that includes SRC-1 and TIF2. TRAM-1 exhibits ligand-dependent, and unexpectedly, AF-2-independent interaction with TR, a biochemical feature distinct from SRC-1/TIF2. Our findings suggest that TRAM-1 may serve a novel pathway for transcr...

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