Adult Drosophila possess a large number of sensory organs, including large and small bristles and other types of sensilla, each arising from a single mother cell at particular positions in a reproducible pattern. Genetic studies have shown that sensory organ pattern formation is partly coordinated by a number of structurally similar, potential heterodimer-forming, helix-loop-helix (HLH) regulatory proteins. Here, by localizing regulatory gene expression during the development of normal and mutant imaginal discs, we show that two positive regulators of sensory neurogenesis, the proneural achaete and scute proteins, initially trans-activate each other and are transiently expressed in identical patterns, including clusters of wing ectodermal cells and the individual sensory mother cells that arise from them. Two negative regulators, hairy and extramacrochaete, suppress sensory neurogenesis by selectively repressing achaete and scute gene expression, respectively, but in different spatial domains and at different developmental stages. Surprisingly, we also find that the level of achaete-scute activity influences the level of ha/ry expression, thereby providing feedback control upon achaete-scute activity and sensory organ formation. Some or all of these interactions may involve specific dimerization reactions between different combinations of HLH proteins.

Summary The mammalian Ajuba LIM proteins (Ajuba, LIMD1, WTIP) are cytosolic adapter proteins that exhibit the potential to communicate cell adhesive events with nuclear responses to remodel epithelia [1] [2]. Determining their role(s) in vivo, however, has been challenging due to overlapping tissue expression and functional redundancy. Thus, we turned to Drosophila where a single gene, CG11063 or djub, exists. Drosophila containing djub mutant loss-of-function alleles or depleted of dJub by RNAi identify djub as an essential gene for development and novel regulator of epithelial organ size as a component of the conserved Hippo pathway, which has been implicated in both tissue size control and cancer development [3-5] [6-9]. djub-deficient tissues were small, had decreased cell numbers as a result of increased apoptosis and decreased proliferation, due to downregulation of DIAP1 and cyclin E. This phenocopies tissues deficient for Yorkie (Yki), the downstream target of the Hippo pathway. djub genetically interacts with the Hippo pathway, and epistasis suggests that djub lies downstream of hpo. In mammalian and Drosophila cells, Ajuba LIM proteins/dJub interact with LATS/Wts and WW45/Sav to inhibit phosphorylation of YAP/Yki. This work describes a novel role for the Ajuba LIM proteins as negative regulators of the Hippo signaling pathway.

Asymmetric cell division is a general process used in many developmental contexts to create two differently fated cells from a single progenitor cell. Intrinsic mechanisms like the asymmetric transmission of cell-fate determinants during cell division, and extrinsic cell-interaction mechanisms, can mediate asymmetric divisions. During embryonic development of the Drosophila central nervous system, neural stem cells called neuroblasts divide asymmetrically to produce another multipotent neuroblast and a ganglion mother cell (GMC) of more restricted developmental potential. Intrinsic mechanisms promote asymmetric division of neuroblasts: for example, the transcription factor Prospero localizes to the basal cell cortex of mitotic neuroblasts and then segregates exclusively into the GMC, which buds off from the basal side of the neuroblast. In the GMC, Prospero translocates to the nucleus, where it establishes differential gene expression between sibling cells. Here we report the identification of a gene, miranda, which encodes a new protein that co-localizes with Prospero in mitotic neuroblasts, tethers Prospero to the basal cortex of mitotic neuroblasts, directing Prospero into the GMC, and releases Prospero from the cell cortex within GMCs. miranda thus creates intrinsic differences between sibling cells by mediating the asymmetric segregation of a transcription factor into only one daughter cell during neural stem-cell division.

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