The cerebellum is essential for fine motor control of movement and posture, and its dysfunction disrupts balance and impairs control of speech, limb and eye movements. The developing cerebellum consists mainly of three types of neuronal cells: granule cells in the external germinal layer, Purkinje cells, and neurons of the deep nuclei. The molecular mechanisms that underlie the specific determination and the differentiation of each of these neuronal subtypes are unknown. Math1, the mouse homologue of the Drosophila gene atonal, encodes a basic helix-loop-helix transcription factor that is specifically expressed in the precursors of the external germinal layer and their derivatives. Here we report that mice lacking Math1 fail to form granule cells and are born with a cerebellum that is devoid of an external germinal layer. To our knowledge, Math1 is the first gene to be shown to be required in vivo for the genesis of granule cells, and hence the predominant neuronal population in the cerebellum.

The multisubunit MSL dosage compensation complex binds to hundreds of sites along the Drosophila single male X chromosome, mediating its hypertranscription. The male X chromosome is also coated with noncoding roX RNAs. When either msl3, mle, or mof is mutant, a partial MSL complex is bound at only approximately 35 unusual sites distributed along the X. We show that two of these sites are the roX1 and roX2 genes and postulate that one of their functions is to provide entry sites for the MSL complex to recognize the X chromosome. The roX1 gene provides a nucleation site for extensive spreading of the MSL complex into flanking chromatin even when moved to an autosome. The spreading can occur in cis or in trans between paired homologs. We present a model for how the dosage compensation complex recognizes X chromatin.

A long-standing model postulates that X-chromosome dosage compensation in Drosophila occurs by twofold up-regulation of the single male X, but previous data cannot exclude an alternative model, in which male autosomes are down-regulated to balance gene expression. To distinguish between the two models, we used RNA interference to deplete Male-Specific Lethal (MSL) complexes from male-like tissue culture cells. We found that expression of many genes from the X chromosome decreased, while expression from the autosomes was largely unchanged. We conclude that the primary role of the MSL complex is to up-regulate the male X chromosome.Supplemental material is available at http://www.genesdev.org.

Our results support a model in which MSL proteins assemble at specific chromatin entry sites (including the roX1 and roX2 genes); the roX RNAs join the complex at their sites of synthesis; and complete complexes spread in cis to dosage compensate most genes on the X chromosome.