Honors & Awards
K99/R00 Pathway to Independence Award, NIH (2020-)
Chinese Government Award for Outstanding Students Abroad, China Scholarship Council (2016)
Doctor of Philosophy, Baylor College Of Medicine (2016)
Bachelor of Science, Tsinghua University (2009)
Liqun Luo, Postdoctoral Faculty Sponsor
Temporal evolution of single-cell transcriptomes of Drosophila olfactory projection neurons.
Neurons undergo substantial morphological and functional changes during development to form precise synaptic connections and acquire specific physiological properties. What are the underlying transcriptomic bases? Here, we obtained the single-cell transcriptomes of Drosophila olfactory projection neurons (PNs) at four developmental stages. We decoded the identity of 21 transcriptomic clusters corresponding to 20 PN types and developed methods to match transcriptomic clusters representing the same PN type across development. We discovered that PN transcriptomes reflect unique biological processes unfolding at each stage-neurite growth and pruning during metamorphosis at an early pupal stage; peaked transcriptomic diversity during olfactory circuit assembly at mid-pupal stages; and neuronal signaling in adults. At early developmental stages, PN types with adjacent birth order share similar transcriptomes. Together, our work reveals principles of cellular diversity during brain development and provides a resource for future studies of neural development in PNs and other neuronal types.
View details for DOI 10.7554/eLife.63450
View details for PubMedID 33427646
Single-cell transcriptomes of developing and adult olfactory receptor neurons in Drosophila.
Recognition of environmental cues is essential for the survival of all organisms. Transcriptional changes occur to enable the generation and function of the neural circuits underlying sensory perception. To gain insight into these changes, we generated single-cell transcriptomes of Drosophila olfactory- (ORNs), thermo-, and hygro-sensory neurons at an early developmental and adult stage using single-cell and single-nucleus RNA sequencing. We discovered that ORNs maintain expression of the same olfactory receptors across development. Using receptor expression and computational approaches, we matched transcriptomic clusters corresponding to anatomically and physiologically defined neuron types across multiple developmental stages. We found that cell-type-specific transcriptomes partly reflected axon trajectory choices in development and sensory modality in adults. We uncovered stage-specific genes that could regulate the wiring and sensory responses of distinct ORN types. Collectively, our data reveal transcriptomic features of sensory neuron biology and provide a resource for future studies of their development and physiology.
View details for DOI 10.7554/eLife.63856
View details for PubMedID 33555999
Cell-Surface Proteomic Profiling in the Fly Brain Uncovers Wiring Regulators.
Molecular interactions at the cellular interface mediate organized assembly of single cells into tissues and, thus, govern the development and physiology of multicellular organisms. Here, we developed a cell-type-specific, spatiotemporally resolved approach to profile cell-surface proteomes in intact tissues. Quantitative profiling of cell-surface proteomes of Drosophila olfactory projection neurons (PNs) in pupae and adults revealed global downregulation of wiring molecules and upregulation of synaptic molecules in the transition from developing to mature PNs. A proteome-instructed invivo screen identified 20 cell-surface molecules regulating neural circuit assembly, many of which belong to evolutionarily conserved protein families not previously linked to neural development. Genetic analysis further revealed that the lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting, contributing to the formation of a precise olfactory map. These findings highlight the power of temporally resolved in situ cell-surface proteomic profiling in discovering regulators of brain wiring.
View details for DOI 10.1016/j.cell.2019.12.029
View details for PubMedID 31955847
Single-Cell Transcriptomes Reveal Diverse Regulatory Strategies for Olfactory Receptor Expression and Axon Targeting.
Current biology : CB
The regulatory mechanisms by which neurons coordinate their physiology and connectivity are not well understood. The Drosophila olfactory receptor neurons (ORNs) provide an excellent system to investigate this question. Each ORN type expresses a unique olfactory receptor, or a combination thereof, and sends their axons to a stereotyped glomerulus. Using single-cell RNA sequencing, we identified 33 transcriptomic clusters for ORNs and mapped 20 to their glomerular types, demonstrating that transcriptomic clusters correspond well with anatomically and physiologically defined ORN types. Each ORN type expresses hundreds of transcription factors. Transcriptome-instructed genetic analyses revealed that (1) one broadly expressed transcription factor (Acj6) only regulates olfactory receptor expression in one ORN type and only wiring specificity in another type, (2) one type-restricted transcription factor (Forkhead) only regulates receptor expression, and (3) another type-restricted transcription factor (Unplugged) regulates both events. Thus, ORNs utilize diverse strategies and complex regulatory networks to coordinate their physiology and connectivity.
View details for DOI 10.1016/j.cub.2020.01.049
View details for PubMedID 32059767
Using Drosophila to study mechanisms of hereditary hearing loss.
Disease models & mechanisms
2018; 11 (6)
Johnston's organ - the hearing organ of Drosophila - has a very different structure and morphology to that of the hearing organs of vertebrates. Nevertheless, it is becoming clear that vertebrate and invertebrate auditory organs share many physiological, molecular and genetic similarities. Here, we compare the molecular and cellular features of hearing organs in Drosophila with those of vertebrates, and discuss recent evidence concerning the functional conservation of Usher proteins between flies and mammals. Mutations in Usher genes cause Usher syndrome, the leading cause of human deafness and blindness. In Drosophila, some Usher syndrome proteins appear to physically interact in protein complexes that are similar to those described in mammals. This functional conservation highlights a rational role for Drosophila as a model for studying hearing, and for investigating the evolution of auditory organs, with the aim of advancing our understanding of the genes that regulate human hearing and the pathogenic mechanisms that lead to deafness.
View details for PubMedID 29853544
Stepwise wiring of the Drosophila olfactory map requires specific Plexin B levels.
View details for DOI 10.7554/eLife.39088.
- Classifying Drosophila Olfactory Projection Neuron Subtypes by Single-Cell RNA Sequencing. Cell 2017; 171 (5)
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdkl/Mef2 activation, leading to neurodegeneration
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.
View details for DOI 10.7554/eLife.16043
View details for PubMedID 27343351
The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals
Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Using a forward genetic screen in Drosophila, we identified an E3 ligase, Ubr3, as an essential gene for auditory organ development. Ubr3 negatively regulates the mono-ubiquitination of non-muscle Myosin II, a protein associated with hearing loss in humans. The mono-ubiquitination of Myosin II promotes its physical interaction with Myosin VIIa, a protein responsible for Usher syndrome type IB. We show that ubr3 mutants phenocopy pathogenic variants of Myosin II and that Ubr3 interacts genetically and physically with three Usher syndrome proteins. The interactions between Myosin VIIa and Myosin IIa are conserved in the mammalian cochlea and in human retinal pigment epithelium cells. Our work reveals a novel mechanism that regulates protein complexes affected in two forms of syndromic deafness and suggests a molecular function for Myosin IIa in auditory organs.
View details for DOI 10.7554/eLife.15258
View details for PubMedID 27331610
Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination
2016; 12 (5)
Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.
View details for DOI 10.1371/journal.pgen.1006054
View details for PubMedID 27195754
Pri sORF peptides induce selective proteasome-mediated protein processing
2015; 349 (6254): 1356-1358
A wide variety of RNAs encode small open-reading-frame (smORF/sORF) peptides, but their functions are largely unknown. Here, we show that Drosophila polished-rice (pri) sORF peptides trigger proteasome-mediated protein processing, converting the Shavenbaby (Svb) transcription repressor into a shorter activator. A genome-wide RNA interference screen identifies an E2-E3 ubiquitin-conjugating complex, UbcD6-Ubr3, which targets Svb to the proteasome in a pri-dependent manner. Upon interaction with Ubr3, Pri peptides promote the binding of Ubr3 to Svb. Ubr3 can then ubiquitinate the Svb N terminus, which is degraded by the proteasome. The C-terminal domains protect Svb from complete degradation and ensure appropriate processing. Our data show that Pri peptides control selectivity of Ubr3 binding, which suggests that the family of sORF peptides may contain an extended repertoire of protein regulators.
View details for DOI 10.1126/science.aac5677
View details for Web of Science ID 000361357700053
View details for PubMedID 26383956
A Drosophila Genetic Resource of Mutants to Study Mechanisms Underlying Human Genetic Diseases
2014; 159 (1): 200-214
Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.
View details for DOI 10.1016/j.cell.2014.09.002
View details for Web of Science ID 000343095000020
View details for PubMedID 25259927
View details for PubMedCentralID PMC4298142
Drosophila EHBP1 regulates Scabrous secretion during Notch-mediated lateral inhibition
JOURNAL OF CELL SCIENCE
2013; 126 (16): 3686-3696
Notch signaling is an evolutionarily conserved pathway that plays a central role in numerous developmental and disease processes. The versatility of the Notch pathway relies on the activity of context-dependent regulators. These include rab11, sec15, arp3 and Drosophila EHBP1 (dEHBP1), which control Notch signaling and cell fate acquisition in asymmetrically dividing mechanosensory lineages by regulating the trafficking of the ligand Delta. Here, we show that dEHBP1 also controls the specification of R8 photoreceptors, as its loss results in the emergence of supernumerary R8 photoreceptors. Given the requirements for Notch signaling during lateral inhibition, we propose that dEHBP1 regulates distinct aspects of Notch signaling in different developmental contexts. We show that dEHBP1 regulates the exocytosis of Scabrous, a positive regulator of Notch signaling. In conclusion, dEHBP1 provides developmental versatility of intercellular signaling by regulating the trafficking of distinct Notch signaling components.
View details for DOI 10.1242/jcs.126292
View details for Web of Science ID 000323204400018
View details for PubMedID 23788431
View details for PubMedCentralID PMC3744027
Crag Is a GEF for Rab11 Required for Rhodopsin Trafficking and Maintenance of Adult Photoreceptor Cells
2012; 10 (12)
Rhodopsins (Rhs) are light sensors, and Rh1 is the major Rh in the Drosophila photoreceptor rhabdomere membrane. Upon photoactivation, a fraction of Rh1 is internalized and degraded, but it remains unclear how the rhabdomeric Rh1 pool is replenished and what molecular players are involved. Here, we show that Crag, a DENN protein, is a guanine nucleotide exchange factor for Rab11 that is required for the homeostasis of Rh1 upon light exposure. The absence of Crag causes a light-induced accumulation of cytoplasmic Rh1, and loss of Crag or Rab11 leads to a similar photoreceptor degeneration in adult flies. Furthermore, the defects associated with loss of Crag can be partially rescued with a constitutive active form of Rab11. We propose that upon light stimulation, Crag is required for trafficking of Rh from the trans-Golgi network to rhabdomere membranes via a Rab11-dependent vesicular transport.
View details for DOI 10.1371/journal.pbio.1001438
View details for Web of Science ID 000312905300002
View details for PubMedID 23226104
View details for PubMedCentralID PMC3514319