Tissue development and RNA control: ‘‘HOW’’ is it coordinated? Talila Volk 1 , David Israeli 1 , Ronit Nir 1 and Hila Toledano-Katchalski 2 1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel 2 The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA 92037, USA The regulation of developmental processes at the RNA level enables selective and rapid modulation of gene expression. Studies in model organisms revealed the essential contribution of the signal transduction and activation of RNA (STAR) family of RNA binding proteins to developmental processes. STAR proteins coordinate the proper timing of developmental events by delaying expression or altering the mRNA or protein levels of essential genes. Recent functional analysis of the Drosophila melanogaster STAR protein, Held Out Wing (HOW), in the context of embryonic development, pro- vided insight into its mode of activity. Here, we describe HOW’s activity in the temporal repression or elevation of gene expression that is essential for coordinating the correct timing of instructive signals. Tissue differentiation and RNA control The development of specific tissues is a multistep process in which cells are first specified and then gradually differ- entiate. The differentiation program must be continuously coordinated as the embryo progresses through sequential developmental stages. Often, the activity of patterning genes, which regulate the development of an entire tissue or organ (e.g. twist in Drosophila regulates mesoderm specification [1,2]), direct the initial assignment of cells into specific lineages during early stages of embryonic development. Tissue differentiation occurs at later devel- opmental stages as additional cellular requirements are fulfilled. For example, cells must migrate into specific positions in the embryo before their final differentiation [3]. The coupling of tissue differentiation to other cellular events, such as migration, that occur during embryonic development requires a mechanism that meets the follow- ing criteria: (i) it should be able to simultaneously regulate the expression of many genes, (ii) it should be sensitive and responsive to external cellular signals and (iii) it should exhibit tissue specificity. Such requirements could be fulfilled by both transcrip- tional and post-transcriptional regulation, either at the RNA or protein level. Notably, regulation at the RNA level might be beneficial in terms of the ability to respond rapidly to signals and the ability to modulate the levels of existing RNA populations in accordance with the temporal requirements within a given tissue. Such a mech- anism could therefore contribute to the selective and regulated expression of gene products whose transcription has already been activated. The control of gene expression is often mediated by RNA-binding proteins (RBPs), which bind to specific sequences within the mRNA target. RBPs control many aspects of RNA metabolism through their association with specific protein complexes in the nucleus or in the cyto- plasm [4,5]. They can regulate the timing and location within the cell of developmental processes by delaying or activating upstream instructive signals. The activity of RBPs depends on their tissue-specific context and is often regulated by post-transcriptional modifications such as phosphorylation or acetylation at specific docking sites [6–8]. Recent data regarding the activity of the RBP protein HOW [a member of the signal transduction and activation of RNA (STAR) protein family] during embryonic devel- opment in Drosophila revealed an intriguing mode of regulation in various tissues. In this review, we will focus on aspects of embryogenesis in Drosophila to show how STAR proteins coordinate diverse morphogenic events. These might serve as a paradigm for the general activities of STAR proteins in development. The STAR family of RNA-binding proteins STAR proteins [9], have been described in various organisms, with homologs in several organisms including Caenorhabditis elegans (GLD-1) [10,11], D. melanogaster (HOW) [12–14] and various mammals (Quaking, QKI) [15]. STAR proteins participate in many aspects of nuclear and cytoplasmic RNA metabolism including mRNA splicing [16–19], localization [20], translation [21–23] and regula- tion of stability [20,24]. The molecular basis for their many distinct activities has yet to be elucidated. All STAR proteins contain a single, highly conserved, maxi K-homology (KH)–RNA binding domain. The KH–RNA binding domain was first characterized in the hetero- geneous ribonucleoprotein, hnRNP K [25]. The maxi KH–RNA binding domain flanks the original KH domain and extends beyond it. Additional conserved domains, known as QUAKING1 (QUA1) and QUAKING2, (QUA2), flank the KH domain [9] (Figure 1). In recent years, much progress has been made in the functional characterization of three STAR family mem- bers: defective in germ line development (Gld-1), QKI and HOW, revealing their critical contribution to the temporal control of tissue development during embryogen- esis (Table 1; Box 1). The identification of several mRNA Review Corresponding author: Volk, T. (lgvolk@weizmann.ac.il). 94 0168-9525/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2007.11.009 Available online 14 January 2008