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Mechanosensation is an evolutionarily ancient sensory modality seen in all main animal groups. Mechanosensation can be mediated by sensory neurons or by dedicated receptor cells that form synapses with sensory neurons. Evidence over the last 15-20 years suggests that both classes of mechanosensory cells can be specified by the atonal class of basic helix-loop-helix transcription factors. In this review we discuss recent work addressing how atonal factors specify mechanosensitive cells in vertebrates and invertebrates, and how the redeployment of these factors underlies the regeneration of mechanosensitive cells in some vertebrate groups.

Summary Cilia have evolved hugely diverse structures and functions to participate in a wide variety of developmental and physiological processes. Ciliary specialization requires differences in gene expression, but few transcription factors are known to regulate this, and their molecular function is unclear. Here, we show that the Drosophila Forkhead box (Fox) gene, fd3F, is required for specialization of the mechanosensory cilium of chordotonal (Ch) neurons. fd3F regulates genes for Ch-specific axonemal dyneins and TRPV ion channels, which are required for sensory transduction, and retrograde transport genes, which are required to differentiate their distinct motile and sensory ciliary zones. fd3F is reminiscent of vertebrate Foxj1, a motile cilia regulator, but fd3F regulates motility genes as part of a broader sensory regulation program. Fd3F cooperates with the pan-ciliary transcription factor, Rfx, to regulate its targets directly. This illuminates pathways involved in ciliary specialization and the molecular mechanism of transcription factors that regulate them., Graphical Abstract Highlights ► Fd3F is a Fox transcription factor for mechanosensory ciliary specialization ► Regulates genes for ciliary motility, compartmentalization, and sensory transduction ► Fd3F modulates the activity of the pan-ciliogenic transcription factor, Rfx ► Fd3F is likely related to Foxj1, the vertebrate regulator of motile ciliated cells, Cilia are highly diverse. The motile sensory cilia of Drosophila mechanosensory neurons provide a good model of ciliary structural and functional specialization. Newton et al. show that Fox and Rfx transcription factors work in concert to activate a gene expression program for ciliary specialization in these neurons.

Using the well-characterised paradigm of Drosophila sensory nervous system development, we examine the functional distinctness of the Amos and Atonal (Ato) proneural transcription factors, which have different mutant phenotypes but share very high similarity in their signature bHLH domains. Using misexpression and mutant rescue assays, we show that Ato and Amos proteins have abundantly distinct intrinsic proneural capabilities in much of the ectoderm. The eye, however, is an exception: here both proteins share the capability to direct the R8 photoreceptor fate choice. Therefore, functional distinctness between these closely related transcription factors varies with developmental context, indicating different molecular mechanisms of specificity in different contexts. Consistent with this, the structural basis for their distinctness also varies depending upon the function in question. In previous studies of neural bHLH factors, specificity invariably mapped to the bHLH domain sequence. Similarly, and despite their high similarity, much of the Amos’ specificity relative to Ato maps to Amos-specific residues in its bHLH domain. For Ato-specific functions, however, the Amos bHLH domain can substitute for that of Ato. Consequently, Ato’s specificity relative to Amos requires the non-bHLH portion of the Ato protein. Ato provides a powerful precedence for a role of non-bHLH sequences in modulating bHLH functional specificity. This has implications for structural and functional comparisons of other closely related transcription factors, and for understanding the molecular basis of specificity.

In Drosophila, commitment of a cell to a sense organ precursor (SOP) fate requires bHLH proneural transcription factor upregulation, a process that depends in most cases on the interplay of proneural gene autoregulation and inhibitory Notch signaling. A subset of SOPs are selected by a recruitment pathway involving EGFR signaling to ectodermal cells expressing the proneural gene atonal. We show that EGFR signaling drives recruitment by directly facilitating atonal autoregulation. Pointed, the transcription factor that mediates EGFR signaling, and Atonal protein itself bind cooperatively to adjacent conserved binding sites in an atonal enhancer. Recruitment is therefore contingent on the combined presence of Atonal protein (providing competence) and EGFR signaling (triggering recruitment). Thus, autoregulation is the nodal control point targeted by signaling. This exemplifies a simple and general mechanism for regulating the transition from competence to cell fate commitment whereby a cell signal directly targets the autoregulation of a selector gene.

SIX5 belongs to a family of highly conserved homeodomain transcription factors implicated in development and disease [1–3]. The mammalian SIX5/SIX4 gene pair is likely to be involved in the development of mesodermal structures [4–6]. Moreover, a variety of data have implicated human SIX5 dysfunction as a contributor to myotonic dystrophy type 1 (DM1), a condition characterized by a number of pathologies including muscle defects and testicular atrophy [7–9]. However, this link remains controversial. Here, we investigate the Drosophila gene, D-Six4 , which is the closest homolog to SIX5 of the three Drosophila Six family members [10]. We show by mutant analysis that D-Six4 is required for the normal development of muscle and the mesodermal component of the gonad. Moreover, adult males with defective D-Six4 genes exhibit testicular reduction. We propose that D-Six4 directly or indirectly regulates genes involved in the cell recognition events required for myoblast fusion and the germline:soma interaction. While the exact phenotypic relationship between D-Six4 and SIX4/5 remains to be elucidated, the defects in D-Six4 mutant flies suggest that human SIX5 should be more strongly considered as being responsible for the muscle wasting and testicular atrophy phenotypes in DM1.

In Drosophila neurogenesis, proneural genes encode bHLH proteins that are required for neural precursor selection. But many vertebrate homologues are expressed later and are postulated to have multiple roles during neurogenesis. We have isolated a new Drosophila gene, cato, which encodes a protein with a bHLH domain that is closely related to that of the proneural protein Atonal. cato expression is restricted to the developing PNS, where it is expressed in between the stages of precursor selection and terminal differentiation (and therefore later than the proneural genes). We present evidence from loss-of-function and misexpression experiments that cato is involved in sensory neurone morphology. Moreover, in prospero mutants, in which axon and dendrite outgrowth is defective, cato is strongly derepressed in the developing CNS.

In a variety of organisms, early neurogenesis requires the function of basic-helix-loop-helix (bHLH) transcription factors. For the Drosophila PNS, such transcription factors are encoded by the proneural genes (atonal and the achaete–scute complex, AS-C). We have identified a proneural gene, amos, that has strong similarity with atonal in its bHLH domain. We present evidence that amos is required for olfactory sensilla and is regulated by the prepattern gene lozenge. Between them, amos, atonal, and the AS-C can potentially account for the origin of the entire PNS.

The proneural genes (atonal and the genes of the achaete–scute complex (AS-C)) are required for the selection of sense organ precursors. They also endow these precursors with sense organ subtype information. In most of the ectoderm, atonal is required for precursors of chordotonal sense organs, whereas AS-C are required for those of most external sense organs, such as bristles. To address the question of how proneural genes influence subtype identity, we have made use of the Gal4/UAS system of misexpression. Unlike previous misexpression experiments, we found that under specific conditions of misexpression, atonal shows high subtype specificity of ectopic sense organ formation. Moreover, atonal can even transform wild-type external sense organs to chordotonal organs, although scute cannot perform the reciprocal transformation. Our evidence demonstrates that atonal's subtype determining role is not to activate directly chordotonal fate, but to repress the activation of cut, a gene that is necessary for external sense organ fate, thereby freeing its precursors to follow the alternative chordotonal organ fate.

The results of a number of recent studies indicate that eye development in insects and vertebrates may have more features in common than hitherto suspected. The results support the possibility that insect and vertebrate eyes evolved from a complex ancestral organ.

Although the control of cell proliferation has been studied intensively at the level of the single cell, less is known about how cell numbers are controlled in developing populations and organs. Often, proliferation provides a pool of cells for organ construction, but the rate of this proliferation must be coordinated with patterning to avoid imbalances in cell numbers. Recent research on the development of the Drosophila eye and the proliferation signals (mitogens) can act to coordinate cell numbers.

It has become apparent in recent years that unexpectedly large numbers of minisatellites exist within the eukaryotic genome. Their use in genetics is well known, but as with any new class of sequence, there is also much speculation about their involvement in a range of biological processes. How much is known of their biology?