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1.  Different ways to make neurons: parallel evolution in the SoxB family 
Genome Biology  2014;15(5):116.
Combining genome-wide analyses of binding sites and expression profiles generates a model for the functional evolution of two SOXB paralogous proteins in neurogenesis.
PMCID: PMC4072935  PMID: 25001546
Neuronal development; SoxB; Functional conservation; Drosophila
2.  Notch activity in neural progenitors coordinates cytokinesis and asymmetric differentiation of neuronal progeny 
Science signaling  2014;7(348):pe26.
Asymmetric cell division of neural progenitors, which involves the segregation of distinct differentiation factors in daughter cells, is a crucial event in the generation of neuronal diversity. In this issue of Science Signaling, Bhat reports a novel role for Notch in promoting asymmetric cell division. While it was previously thought that Notch acts post mitotically in response to its negative regulator, Numb to promote cell fate, Notch in fact appears to act before cell division to promote asymmetric cytokinesis and differentiation by regulating Numb localization in precursor cells. As Numb also regulates Notch activity, this forms a regulatory feedback loop.
PMCID: PMC4243685  PMID: 25336612
3.  Processing properties of ON and OFF pathways for Drosophila motion detection 
Nature  2014;512(7515):427-430.
The algorithms and neural circuits that process spatiotemporal changes in luminance to extract visual motion cues have been the focus of intense research. An influential model, the Hassenstein-Reichardt correlator1 (HRC), relies on differential temporal filtering of two spatially separated input channels, delaying one input signal with respect to the other. Motion in a particular direction causes these delayed and non-delayed luminance signals to arrive simultaneously at a subsequent processing step in the brain; these signals are then nonlinearly amplified to produce a direction-selective response (Figure 1A). Recent work in Drosophila has identified two parallel pathways that selectively respond to either moving light or dark edges2,3. Each of these pathways requires two critical processing steps to be applied to incoming signals: differential delay between the spatial input channels, and distinct processing of brightness increment and decrement signals. Using in vivo patch-clamp recordings, we demonstrate that four medulla neurons implement these two processing steps. The neurons Mi1 and Tm3 respond selectively to brightness increments, with the response of Mi1 delayed relative to Tm3. Conversely, Tm1 and Tm2 respond selectively to brightness decrements, with the response of Tm1 delayed compared to Tm2. Remarkably, constraining HRC models using these measurements produces outputs consistent with previously measured properties of motion detectors, including temporal frequency tuning and specificity for light vs. dark edges. We propose that Mi1 and Tm3 perform critical processing of the delayed and non-delayed input channels of the correlator responsible for the detection of light edges, while Tm1 and Tm2 play analogous roles in the detection of moving dark edges. Our data shows that specific medulla neurons possess response properties that allow them to implement the algorithmic steps that precede the correlative operation in the HRC, revealing elements of the long-sought neural substrates of motion detection in the fly.
PMCID: PMC4243710  PMID: 25043016
4.  Opposing Feedbacks on Ras Tune RTK Signaling 
Science signaling  2013;6(300):pe35.
Signaling in development is not always on or off; often, distinct intensity and duration of signaling leads to distinct outcomes. This is true for receptor-tyrosine-kinase (RTK) signaling in many contexts, where negative feedback often plays a role. Although such negative feedback might reduce or even turn off signaling output over time, continued signaling is often maintained for proper cell fate specification. In this issue, Sieglitz et al. identify a positive regulator of Ras-mediated RTK signaling that they name Rau. Rau is necessary to achieve specific signaling intensity for the differentiation of photoreceptors and of glia that wrap axons in the developing Drosophila eye disc. Both the negative regulator Sprouty and Rau influence signaling through the GTPase Ras: Rau forms a positive feedback loop important for counteracting the Sprouty negative feedback loop.
PMCID: PMC4136755  PMID: 24194582
5.  Conserved miR-8/miR-200 Defines a Glial Niche that Controls Neuroepithelial Expansion and Neuroblast Transition 
Developmental cell  2013;27(2):174-187.
Neuroepithelial cell proliferation must be carefully balanced with the transition to neuroblast (neural stem cell) to control neurogenesis. Here, we show that loss of the Drosophila microRNA mir-8 (the homolog of vertebrate miR-200 family) results in both excess proliferation and ectopic neuroblast transition. Unexpectedly, mir-8 is expressed in a subpopulation of optic-lobe-associated cortex glia that extend processes that ensheath the neuroepithelium, suggesting that glia cells communicate with the neuroepithelium. We provide evidence that miR-8-positive glia express Spitz, a transforming growth factor α (TGF-α)-like ligand that triggers epidermal growth factor receptor (EGFR) activation to promote neuroepithelial proliferation and neuroblast formation. Further, our experiments suggest that miR-8 ensures both a correct glial architecture and the spatiotemporal control of Spitz protein synthesis via direct binding to Spitz 3′ UTR. Together, these results establish glial-derived cues as key regulatory elements in the control of neuroepithelial cell proliferation and the neuroblast transition.
PMCID: PMC3931912  PMID: 24139822
6.  Opposite Feedbacks in the Hippo Pathway for Growth Control and Neural Fate 
Science (New York, N.Y.)  2013;342(6155):1238016.
Signaling pathways are re-used for multiple purposes in plant and animal development. The Hippo pathway in mammals and Drosophila coordinates proliferation and apoptosis via the co-activator and oncogene, YAP/Yorkie (Yki), which is homeostatically regulated through negative feedback. In the Drosophila eye, cross-repression between the Hippo pathway kinase, LATS/Warts (Wts), and growth regulator, Melted, generates mutually exclusive photoreceptor subtypes. Here, we show that this all-or-nothing neuronal differentiation results from Hippo pathway positive feedback: Yki both represses its negative regulator, warts, and promotes its positive regulator, melted. This post-mitotic Hippo network behavior relies on a tissue-restricted transcription factor network—including a conserved Otx/Orthodenticle-Nrl/Traffic Jam feedforward module—that allows Warts-Yki-Melted to operate as a bistable switch. Altering feedback architecture provides an efficient mechanism to co-opt conserved signaling networks for diverse purposes in development and evolution.
PMCID: PMC3796000  PMID: 23989952
7.  The neuronal transcription factor Erect wing regulates specification and maintenance of Drosophila R8 photoreceptor subtypes 
Developmental biology  2013;381(2):482-490.
Signaling pathways are often re-used during development in surprisingly different ways. The Hippo tumor suppressor pathway is best understood for its role in the control of growth. The Hippo pathway is also used in a very different context, in the Drosophila eye for the robust specification of R8 photoreceptor neuron subtypes, which complete their terminal differentiation by expressing light-sensing Rhodopsin (Rh) proteins. A double negative feedback loop between the Warts kinase of the Hippo pathway and the PH-domain growth regulator Melted regulates the choice between `pale' R8 (pR8) fate defined by Rh5 expression and `yellow' R8 (yR8) fate characterized by Rh6 expression. Here, we show that the gene encoding the homologue of human Nuclear respiratory factor 1, erect wing (ewg), is autonomously required to repress warts and to promote melted expression to specify pR8 subtype fate and induce Rh5 expression. ewg mutants express Rh6 in most R8s due to ectopic warts expression. Further, ewg is continuously required to maintain repression of Rh6 in pR8s in aging flies. Our work shows that Ewg is a critical factor for the stable down-regulation of Hippo pathway activity to determine neuronal subtype fates. Neural-enriched factors, such as Ewg, may generally contribute to the contextual re-use of signaling pathways in post-mitotic neurons.
PMCID: PMC3757101  PMID: 23850772
8.  Sensory Cell Fates: Four Defaults for the Price of One 
Current biology : CB  2013;23(24):R1089-R1091.
The specification of different subtypes of olfactory sensilla, which harbor the olfactory receptor neurons (ORNs) in the Drosophila antennae, is poorly understood. Loss of the transcription factor Rotund (Rn) leads to a simultaneous mis-specification of several ORN classes, transforming them into different ‘default’ cell fates.
PMCID: PMC4134906  PMID: 24355782
9.  Interchromosomal communication coordinates intrinsically stochastic expression between alleles 
Science (New York, N.Y.)  2014;343(6171):661-665.
Sensory systems use stochastic mechanisms to diversify neuronal subtypes. In the Drosophila eye, stochastic expression of the PAS-bHLH transcription factor Spineless (Ss) determines a random binary subtype choice in R7 photoreceptors. Here, we show that a stochastic, cell-autonomous decision to express ss is made intrinsically by each ss locus. Stochastic on or off expression of each ss allele is determined by combinatorial inputs from one enhancer and two silencers acting at long range. However, the two ss alleles also average their frequency of expression through upregulatory and downregulatory interallelic cross-talk. This inter- or intra-chromosomal long-range regulation does not require endogenous ss chromosomal positioning or pairing. Therefore, although individual ss alleles make independent stochastic choices, interchromosomal communication coordinates expression state between alleles, ensuring that they are both expressed in the same random subset of R7s.
PMCID: PMC4134473  PMID: 24503853
10.  Dissection and Immunohistochemistry of Larval, Pupal and Adult Drosophila Retinas 
The compound eye of Drosophila melanogaster consists of about 750 ommatidia (unit eyes). Each ommatidium is composed of about 20 cells, including lens-secreting cone cells, pigment cells, a bristle cell and eight photoreceptors (PRs) R1-R8 2. The PRs have specialized microvillar structures, the rhabdomeres, which contain light-sensitive pigments, the Rhodopsins (Rhs). The rhabdomeres of six PRs (R1-R6) form a trapezoid and contain Rh1 34. The rhabdomeres of R7 and R8 are positioned in tandem in the center of the trapezoid and share the same path of light. R7 and R8 PRs stochastically express different combinations of Rhs in two main subtypes5: In the ‘p’ subtype, Rh3 in pR7s is coupled with Rh5 in pR8s, whereas in the ‘y’ subtype, Rh4 in yR7s is associated with Rh6 in yR8s 678.
Early specification of PRs and development of ommatidia begins in the larval eye-antennal imaginal disc, a monolayer of epithelial cells. A wave of differentiation sweeps across the disc9 and initiates the assembly of undifferentiated cells into ommatidia10-11. The ‘founder cell’ R8 is specified first and recruits R1-6 and then R7 12-14. Subsequently, during pupal development, PR differentiation leads to extensive morphological changes15, including rhabdomere formation, synaptogenesis and eventually rh expression.
In this protocol, we describe methods for retinal dissections and immunohistochemistry at three defined periods of retina development, which can be applied to address a variety of questions concerning retinal formation and developmental pathways. Here, we use these methods to visualize the stepwise PR differentiation at the single-cell level in whole mount larval, midpupal and adult retinas (Figure 1).
PMCID: PMC3523422  PMID: 23183823
Neuroscience; Issue 69; Anatomy; Physiology; Immunology; Developmental Biology; Drosophila; retina; photoreceptor; imaginal disc; larva; pupa; confocal microscopy; immunohistochemistry
11.  Regional modulation of a stochastically expressed factor determines photoreceptor subtypes in the Drosophila retina 
Developmental cell  2013;25(1):93-105.
Stochastic mechanisms are sometimes utilized to diversify cell fates, especially in nervous systems. In the Drosophila retina, stochastic expression of the PAS-bHLH transcription factor Spineless (Ss) controls photoreceptor subtype choice. In one randomly distributed subset of R7 photoreceptors, Ss activates Rhodopsin4 (Rh4) and represses Rhodopsin3 (Rh3); counterparts lacking Ss express Rh3 and repress Rh4. In the dorsal third region of the retina, the Iroquois Complex transcription factors induce Rh3 in Rh4-expressing R7s. Here, we show that Ss levels are controlled in a binary On/Off manner throughout the retina, yet are attenuated in the dorsal third region to allow Rh3 co-expression with Rh4. Whereas the sensitivity of rh3 repression to differences in Ss levels generates stochastic and regionalized patterns, the robustness of rh4 activation ensures its stochastic expression throughout the retina. Our findings show how stochastic and regional inputs are integrated to control photoreceptor subtype specification in the Drosophila retina.
PMCID: PMC3660048  PMID: 23597484
12.  Genetic Dissection of Photoreceptor Subtype Specification by the Drosophila melanogaster Zinc Finger Proteins Elbow and No ocelli 
PLoS Genetics  2014;10(3):e1004210.
The elbow/no ocelli (elb/noc) complex of Drosophila melanogaster encodes two paralogs of the evolutionarily conserved NET family of zinc finger proteins. These transcriptional repressors share a conserved domain structure, including a single atypical C2H2 zinc finger. In flies, Elb and Noc are important for the development of legs, eyes and tracheae. Vertebrate NET proteins play an important role in the developing nervous system, and mutations in the homolog ZNF703 human promote luminal breast cancer. However, their interaction with transcriptional regulators is incompletely understood. Here we show that loss of both Elb and Noc causes mis-specification of polarization-sensitive photoreceptors in the ‘dorsal rim area’ (DRA) of the fly retina. This phenotype is identical to the loss of the homeodomain transcription factor Homothorax (Hth)/dMeis. Development of DRA ommatidia and expression of Hth are induced by the Wingless/Wnt pathway. Our data suggest that Elb/Noc genetically interact with Hth, and we identify two conserved domains crucial for this function. Furthermore, we show that Elb/Noc specifically interact with the transcription factor Orthodenticle (Otd)/Otx, a crucial regulator of rhodopsin gene transcription. Interestingly, different Elb/Noc domains are required to antagonize Otd functions in transcriptional activation, versus transcriptional repression. We propose that similar interactions between vertebrate NET proteins and Meis and Otx factors might play a role in development and disease.
Author Summary
The eyes of many animals contain groups of photoreceptor cells with different chromatic sensitivities that can be arranged in complex patterns. It is of great interest to identify the genes and pathways shaping these ‘retinal mosaics’ which include stochastically distributed groups of cells, versus highly localized ones. In many insect eyes, which are composed of large numbers of unit eyes, or ommatidia, specialized photoreceptors are found only in the dorsal periphery, where they face the sky. These ommatidia are responsible for detecting linearly polarized skylight, which serves as an important navigational cue for these animals. Here we describe how two closely related proteins called Elbow and No ocelli interact with the transcription factors Homothorax and Orthodenticle to correctly specify the polarization detectors at the dorsal rim of the retina of Drosophila melanogaster. Interestingly, all four proteins are evolutionarily conserved from worms to humans, and they appear to be involved in similar developmental processes across species. Furthermore, human homologs of Elbow and No ocelli have been identified as promoters of luminal breast cancer. The newly identified role of these two proteins within a regulatory network might therefore enable new approaches in a number of important processes.
PMCID: PMC3953069  PMID: 24625735
13.  Dual mode of embryonic development is highlighted by expression and function of Nasonia pair-rule genes 
eLife  2014;3:e01440.
Embryonic anterior–posterior patterning is well understood in Drosophila, which uses ‘long germ’ embryogenesis, in which all segments are patterned before cellularization. In contrast, most insects use ‘short germ’ embryogenesis, wherein only head and thorax are patterned in a syncytial environment while the remainder of the embryo is generated after cellularization. We use the wasp Nasonia (Nv) to address how the transition from short to long germ embryogenesis occurred. Maternal and gap gene expression in Nasonia suggest long germ embryogenesis. However, the Nasonia pair-rule genes even-skipped, odd-skipped, runt and hairy are all expressed as early blastoderm pair-rule stripes and late-forming posterior stripes. Knockdown of Nv eve, odd or h causes loss of alternate segments at the anterior and complete loss of abdominal segments. We propose that Nasonia uses a mixed mode of segmentation wherein pair-rule genes pattern the embryo in a manner resembling Drosophila at the anterior and ancestral Tribolium at the posterior.
eLife digest
Networks of genes that work together are widespread in nature. The conservation of individual genes across species and the tendency of their networks to stick together is a sign that they are working efficiently. Furthermore, it is common for existing gene networks to be adapted to perform new tasks, instead of new networks being invented every time a similar but distinct demand arises. One important question is: how can evolution use the same building blocks—such as the genes in a functioning network—in different ways to achieve new outcomes?
The gene network that sets up the ‘body plan’ of insects during development has been well studied, most deeply in the fruit fly, Drosophila. Like all insects, the body of a fruit fly is divided into three main parts—the head, the thorax and the abdomen—and each of these parts is made up of several smaller segments. There is a remarkable diversity of insect body plans in nature, and yet, these seem to arise from the same gene networks in the embryo.
When a Drosophila embryo is growing into a larva, all the different body segments develop at the same time. In most other insects, however, segments of the abdomen emerge later and sequentially during the development process. The ancestors of most insects are also thought to have developed in this way, which is known as ‘short germ embryogenesis’. So how did the so-called ‘long germ embryogenesis’, as observed in Drosophila, evolve from the short germ embryogenesis that is observed in most other insects?
The gene network that controls development includes the ‘pair-rule genes’ that are expressed in a pattern of alternating stripes that wrap around, top to bottom, along most of the length of the embryo. These stripes mark where the edges of each body segment will eventually develop. In fruit flies, this pattern extends along the entire length of the embryo and the stripes all appear at one time. However, in the abdominal region of short germ insects, the pair-rule genes are expressed in waves that pass through the posterior region as it grows, with new segments being added one behind the other.
Now, Rosenberg et al. have attempted to explain how the same genes can be used to direct the segmentation process in such different ways by studying another long germ insect species, the jewel wasp. Analysis of the expression of pair-rule genes in the jewel wasp shows that it uses a mixed strategy to control segmentation. The development of segments at the front of its body is directed in the same way as the fruit fly, with all these segments laid down together. However, the segments at the rear of the body are only patterned later, one after the other, like most other insects.
The work of Rosenberg et al. suggests that the jewel wasp represents an intermediate step between ancestral insects and Drosophila in the evolution of the gene network that patterns the ‘body plan’. Identifying and studying these intermediate forms allows us to understand the ways in which evolution can innovate by building upon what has come before.
PMCID: PMC3941026  PMID: 24599282
Nasonia vitripennis; Tribolium; embryonic patterning; evolution; segmentation; pair-rule genes; D. melanogaster; other
14.  Dying to Entrain: Regulating ipRGC Spacing 
Developmental cell  2013;24(4):338-340.
In a recent issue of Neuron,Chen et al. (2013) show that apoptosis is required to ensure the even distribution of a class of retinal ganglion cells (ipRGCs), which sense luminance both intrinsically and through input from rods and cones. Disrupting apoptosis impairs photoentrainment mediated by rods/cones, but not that mediated by ipRGC-expressed melanopsin.
PMCID: PMC3744582  PMID: 23449468
15.  Temporal Patterning of Neural Progenitors in Drosophila 
Drosophila has recently become a powerful model system to understand the mechanisms of temporal patterning of neural progenitors called neuroblasts (NBs). Two different temporal sequences of transcription factors (TFs) have been found to be sequentially expressed in NBs of two different systems: the Hunchback, Krüppel, Pdm1/Pdm2, Castor, and Grainyhead sequence in the Drosophila ventral nerve cord; and the Homothorax, Klumpfuss, Eyeless, Sloppy-paired, Dichaete, and Tailless sequence that patterns medulla NBs. In addition, the intermediate neural progenitors of type II NB lineages are patterned by a different sequence: Dichaete, Grainyhead, and Eyeless. These three examples suggest that temporal patterning of neural precursors by sequences of TFs is a common theme to generate neural diversity. Cross-regulations, including negative feedback regulation and positive feedforward regulation among the temporal factors, can facilitate the progression of the sequence. However, there are many remaining questions to understand the mechanism of temporal transitions. The temporal sequence progression is intimately linked to the progressive restriction of NB competence, and eventually determines the end of neurogenesis. Temporal identity has to be integrated with spatial identity information, as well as with the Notch-dependent binary fate choices, in order to generate specific neuron fates.
PMCID: PMC3927947  PMID: 23962839
16.  Temporal patterning of Drosophila medulla neuroblasts controls neural fates 
Nature  2013;498(7455):456-462.
In the Drosophila optic lobes, the medulla processes visual information coming from inner photoreceptors R7 and R8 and from lamina neurons. It contains ~40,000 neurons belonging to over 70 different types. We describe how precise temporal patterning of neural progenitors generates these different neural types. Five transcription factors--Homothorax, Eyeless, Sloppy-paired, Dichaete and Tailless--are sequentially expressed in a temporal cascade in each of the medulla neuroblasts as they age. Loss of either Eyeless, Sloppy-paired or Dichaete blocks further progression of the temporal sequence. We provide evidence that this temporal sequence in neuroblasts, together with Notch-dependent binary fate choice, controls the diversification of the neuronal progeny. Although a temporal sequence of transcription factors had been identified in Drosophila embryonic neuroblasts, our work illustrates the generality of this strategy, with different sequences of transcription factors being used in different contexts.
PMCID: PMC3701960  PMID: 23783517
17.  Stochastic spineless expression creates the retinal mosaic for colour vision 
Nature  2006;440(7081):10.1038/nature04615.
Drosophila colour vision is achieved by R7 and R8 photoreceptor cells present in every ommatidium. The fly retina contains two types of ommatidia, called ‘pale’ and ‘yellow’, defined by different rhodopsin pairs expressed in R7 and R8 cells. Similar to the human cone photoreceptors, these ommatidial subtypes are distributed stochastically in the retina. The choice between pale versus yellow ommatidia is made in R7 cells, which then impose their fate onto R8. Here we report that the Drosophila dioxin receptor Spineless is both necessary and sufficient for the formation of the ommatidial mosaic. A short burst of spineless expression at mid-pupation in a large subset of R7 cells precedes rhodopsin expression. In spineless mutants, all R7 and most R8 cells adopt the pale fate, whereas overexpression of spineless is sufficient to induce the yellow R7 fate. Therefore, this study suggests that the entire retinal mosaic required for colour vision is defined by the stochastic expression of a single transcription factor, Spineless.
PMCID: PMC3826883  PMID: 16525464
18.  Deterministic or stochastic choices in retinal neuron specification 
Neuron  2012;75(5):739-742.
There are two views on vertebrate retinogenesis: a deterministic model dependent on fixed lineages, and a stochastic model in which choices of division modes and cell fates cannot be predicted. In this issue of Neuron, He et al. (2012) address this question in zebra fish using live imaging and mathematical modeling.
PMCID: PMC3438524  PMID: 22958814
vertebrate retinogenesis; competence; stochasticity; retinal progenitor; birth order
19.  Power tools for gene expression and clonal analysis in Drosophila 
Nature methods  2011;9(1):47-55.
The development of two-component expression systems in Drosophila melanogaster, one of the most powerful genetic models, has allowed the precise manipulation of gene function in specific cell populations. These expression systems, in combination with site-specific recombination approaches, have also led to the development of new methods for clonal lineage analysis. We present a hands-on user guide to the techniques and approaches that have greatly increased resolution of genetic analysis in the fly, with a special focus on their application for lineage analysis. Our intention is to provide guidance and suggestions regarding which genetic tools are most suitable for addressing different developmental questions.
PMCID: PMC3574576  PMID: 22205518
21.  The retinal mosaics of opsin expression in invertebrates and vertebrates 
Developmental neurobiology  2011;71(12):1212-1226.
Colour vision is found in many invertebrate and vertebrate species. It is the ability to discriminate objects based on the wavelength of emitted light independent of intensity. As it requires the comparison of at least two photoreceptor types with different spectral sensitivities, this process is often mediated by a mosaic made of several photoreceptor types. In this review, we summarize the current knowledge about the formation of retinal mosaics and the regulation of photopigment (opsin) expression in the fly, mouse and human retina. Despite distinct evolutionary origins, as well as major differences in morphology and phototransduction machineries, there are significant similarities in the stepwise cell-fate decisions that lead from progenitor cells to terminally differentiated photoreceptors that express a particular opsin. Common themes include i) the use of binary transcriptional switches that distinguish classes of photoreceptors, ii) the use of gradients of signaling molecules for regional specializations, iii) stochastic choices that pattern the retina and iv) the use of permissive factors with multiple roles in different photoreceptor types.
PMCID: PMC3190030  PMID: 21557510
photoreceptor; opsin; colour vision; retinal mosaic; transcription factors
22.  Binary Regulation of Hippo Pathway by Merlin/NF2, Kibra, Lgl, and Melted Specifies and Maintains Post-mitotic Neuronal Fate 
Developmental cell  2011;21(5):874-887.
Patterning the Drosophila retina for color vision relies on post-mitotic specification of photoreceptor subtypes. R8 photoreceptors express one of two light-sensing Rhodopsins, Rh5 or Rh6. This fate decision involves a bistable feedback loop between Melted, a PH-domain protein, and Warts, a kinase in the Hippo growth pathway. Here, we show a subset of the Hippo pathway—Merlin(Mer), Kibra(Kib), and Lethal(2)giant larvae(Lgl), but not Expanded or Fat--is required for Warts expression and activity in R8 to specify Rh6 fate. Melted represses warts transcription to disrupt Hippo pathway activity and specify Rh5 fate. R8 Hippo signaling therefore exhibits ON-or-OFF regulation, promoting mutually exclusive fates. Furthermore, Mer and Lgl are continuously required to maintain R8 neuronal subtypes. These results reveal a role for Mer, Kib, and Lgl in neuronal specification and maintenance, and show that the Hippo pathway is re-implemented for sensory neuron fate by combining canonical and non-canonical regulatory steps.
PMCID: PMC3215849  PMID: 22055343
binary cell fate; color vision; photoreceptor; rhodopsin; Hippo pathway; neural development; neural maintenance; Merlin; Warts; Kibra; Lgl
23.  Interlocked feedforward loops control cell type-specific Rhodopsin expression in the Drosophila eye 
Cell  2011;145(6):956-968.
How complex networks of activators and repressors lead to exquisitely specific cell type determination during development is poorly understood. In the Drosophila eye, expression patterns of Rhodopsins define at least eight functionally distinct though related subtypes of photoreceptors. Here, we describe a role for the transcription factor gene defective proventriculus (dve) as a critical node in the network regulating Rhodopsin expression. dve is a shared component of two opposing, interlocked feedforward loops (FFLs). Orthodenticle and Dve interact in an incoherent FFL to repress Rhodopsin expression throughout the eye. In the R7 and R8 photoreceptors, a coherent FFL relieves repression by Dve while activating Rhodopsin expression. Therefore, this network uses repression to restrict, and combinatorial activation to induce cell type-specific expression. Further, Dve levels are finely tuned to yield cell type- and region-specific repression or activation outcomes. This interlocked FFL motif may be a general mechanism to control terminal cell fate specification.
PMCID: PMC3117217  PMID: 21663797
24.  Feedback from Rhodopsin controls rhodopsin exclusion in Drosophila photoreceptors 
Nature  2011;479(7371):108-112.
Sensory systems with high discriminatory power employ neurons that express only one of several alternative sensory receptor proteins. This exclusive receptor gene expression restricts the sensitivity spectrum of neurons and is coordinated with the choice of their synaptic targets1-3. However, little is known about how it is maintained throughout the life of a neuron. Here we show that the green-light sensing receptor Rhodopsin 6 (Rh6) acts to exclude an alternative blue-sensitive Rhodopsin 5 (Rh5) from a subset of Drosophila R8 photoreceptor neurons4. Loss of Rh6 leads to a gradual expansion of Rh5 expression into all R8 photoreceptors of the aging adult retina. The Rh6 feedback signal results in repression of the rh5 promoter and can be mimicked by other Drosophila Rhodopsins; it is partially dependent on activation of Rhodopsin by light, and relies on Gαq activity, but not on the subsequent steps of the phototransduction cascade5. Our observations reveal a thus far unappreciated spectral plasticity of R8 photoreceptors, and identify Rhodopsin feedback as an exclusion mechanism.
PMCID: PMC3208777  PMID: 21983964
25.  Stochastic Mechanisms of Cell Fate Specification that Yield Random or Robust Outcomes 
Although cell fate specification is tightly controlled to yield highly reproducible results and avoid extreme variation, developmental programs often incorporate stochastic mechanisms to diversify cell types. Stochastic specification phenomena are observed in a wide range of species and an assorted set of developmental contexts. In bacteria, stochastic mechanisms are utilized to generate transient subpopulations capable of surviving adverse environmental conditions. In vertebrate, insect, and worm nervous systems, stochastic fate choices are used to increase the repertoire of sensory and motor neuron subtypes. Random fate choices are also integrated into developmental programs controlling organogenesis. Although stochastic decisions can be maintained to produce a mosaic of fates within a population of cells, they can also be compensated for or directed to yield robust and reproducible outcomes.
PMCID: PMC3025287  PMID: 20590453
bet-hedging; color vision; olfaction; spinal cord; lateral inhibition

Results 1-25 (45)