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Article ; Online: Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism.

Sun, Y Henry / Wu, Yueh-Lin / Liao, Ben-Yang

2023 Volume 30, Issue 1, Page(s) 58

Abstract: Phenotypic heterogeneity is very common in genetic systems and in human diseases and has important consequences for disease diagnosis and treatment. In addition to the many genetic and non-genetic (e.g., epigenetic, environmental) factors reported to ... ...

Abstract	Phenotypic heterogeneity is very common in genetic systems and in human diseases and has important consequences for disease diagnosis and treatment. In addition to the many genetic and non-genetic (e.g., epigenetic, environmental) factors reported to account for part of the heterogeneity, we stress the importance of stochastic fluctuation and regulatory network topology in contributing to phenotypic heterogeneity. We argue that a threshold effect is a unifying principle to explain the phenomenon; that ultrasensitivity is the molecular mechanism for this threshold effect; and discuss the three conditions for phenotypic heterogeneity to occur. We suggest that threshold effects occur not only at the cellular level, but also at the organ level. We stress the importance of context-dependence and its relationship to pleiotropy and edgetic mutations. Based on this model, we provide practical strategies to study human genetic diseases. By understanding the network mechanism for ultrasensitivity and identifying the critical factor, we may manipulate the weak spot to gently nudge the system from an ultrasensitive state to a stable non-disease state. Our analysis provides a new insight into the prevention and treatment of genetic diseases.
MeSH term(s)	Humans ; Mutation ; Phenotype ; Genetic Diseases, Inborn
Language	English
Publishing date	2023-07-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-023-00959-7
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Article ; Online: Early lineage segregation of the retinal basal glia in the Drosophila eye disc.

Tsao, Chia-Kang / Huang, Yu Fen / Sun, Y Henry

Scientific reports

2020 Volume 10, Issue 1, Page(s) 18522

Abstract: The retinal basal glia (RBG) is a group of glia that migrates from the optic stalk into the third instar larval eye disc while the photoreceptor cells (PR) are differentiating. The RBGs are grouped into three major classes based on molecular and ... ...

Abstract	The retinal basal glia (RBG) is a group of glia that migrates from the optic stalk into the third instar larval eye disc while the photoreceptor cells (PR) are differentiating. The RBGs are grouped into three major classes based on molecular and morphological characteristics: surface glia (SG), wrapping glia (WG) and carpet glia (CG). The SGs migrate and divide. The WGs are postmitotic and wraps PR axons. The CGs have giant nucleus and extensive membrane extension that each covers half of the eye disc. In this study, we used lineage tracing methods to determine the lineage relationships among these glia subtypes and the temporal profile of the lineage decisions for RBG development. We found that the CG lineage segregated from the other RBG very early in the embryonic stage. It has been proposed that the SGs migrate under the CG membrane, which prevented SGs from contacting with the PR axons lying above the CG membrane. Upon passing the front of the CG membrane, which is slightly behind the morphogenetic furrow that marks the front of PR differentiation, the migrating SG contact the nascent PR axon, which in turn release FGF to induce SGs' differentiation into WG. Interestingly, we found that SGs are equally distributed apical and basal to the CG membrane, so that the apical SGs are not prevented from contacting PR axons by CG membrane. Clonal analysis reveals that the apical and basal RBG are derived from distinct lineages determined before they enter the eye disc. Moreover, the basal SG lack the competence to respond to FGFR signaling, preventing its differentiation into WG. Our findings suggest that this novel glia-to-glia differentiation is both dependent on early lineage decision and on a yet unidentified regulatory mechanism, which can provide spatiotemporal coordination of WG differentiation with the progressive differentiation of photoreceptor neurons.
MeSH term(s)	Animals ; Axons/metabolism ; Cell Differentiation/physiology ; Cell Movement ; Drosophila Proteins/metabolism ; Drosophila melanogaster/embryology ; Drosophila melanogaster/metabolism ; Morphogenesis/physiology ; Neurogenesis/physiology ; Neuroglia/metabolism ; Neuroglia/physiology ; Neurons/metabolism ; Optic Disk/embryology ; Optic Disk/metabolism ; Photoreceptor Cells, Invertebrate/physiology ; Retina/embryology ; Retina/metabolism ; Signal Transduction/physiology
Chemical Substances	Drosophila Proteins
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-75581-w
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Article ; Online: Notch-dependent epithelial fold determines boundary formation between developmental fields in the Drosophila antenna.

Ku, Hui-Yu / Sun, Y Henry

PLoS genetics

2017 Volume 13, Issue 7, Page(s) e1006898

Abstract: Compartment boundary formation plays an important role in development by separating adjacent developmental fields. Drosophila imaginal discs have proven valuable for studying the mechanisms of boundary formation. We studied the boundary separating the ... ...

Abstract	Compartment boundary formation plays an important role in development by separating adjacent developmental fields. Drosophila imaginal discs have proven valuable for studying the mechanisms of boundary formation. We studied the boundary separating the proximal A1 segment and the distal segments, defined respectively by Lim1 and Dll expression in the eye-antenna disc. Sharp segregation of the Lim1 and Dll expression domains precedes activation of Notch at the Dll/Lim1 interface. By repressing bantam miRNA and elevating the actin regulator Enable, Notch signaling then induces actomyosin-dependent apical constriction and epithelial fold. Disruption of Notch signaling or the actomyosin network reduces apical constriction and epithelial fold, so that Dll and Lim1 cells become intermingled. Our results demonstrate a new mechanism of boundary formation by actomyosin-dependent tissue folding, which provides a physical barrier to prevent mixing of cells from adjacent developmental fields.
MeSH term(s)	Animals ; Arthropod Antennae/growth & development ; Cloning, Molecular ; Drosophila/embryology ; Drosophila/genetics ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Epithelial Cells/metabolism ; Gene Expression Regulation, Developmental ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Image Processing, Computer-Assisted ; LIM-Homeodomain Proteins/genetics ; LIM-Homeodomain Proteins/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Protein Folding ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Wings, Animal/growth & development
Chemical Substances	Drosophila Proteins ; Homeodomain Proteins ; LIM-Homeodomain Proteins ; LIM1 protein, Drosophila ; MicroRNAs ; N protein, Drosophila ; Receptors, Notch ; Transcription Factors ; distal-less protein, insect
Language	English
Publishing date	2017-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1006898
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Article ; Online: Isoform-specific functions of an evolutionarily conserved 3 bp micro-exon alternatively spliced from another exon in Drosophila homothorax gene.

Chang, Ling-Wen / Tseng, I-Chieh / Wang, Lan-Hsin / Sun, Y Henry

Scientific reports

2020 Volume 10, Issue 1, Page(s) 12783

Abstract: Micro-exons are exons of very small size (usually 3-30 nts). Some micro-exons are alternatively spliced. Their functions, regulation and evolution are largely unknown. Here, we present an example of an alternatively spliced 3 bp micro-exon (micro-Ex8) in ...

Abstract	Micro-exons are exons of very small size (usually 3-30 nts). Some micro-exons are alternatively spliced. Their functions, regulation and evolution are largely unknown. Here, we present an example of an alternatively spliced 3 bp micro-exon (micro-Ex8) in the homothorax (hth) gene in Drosophila. Hth is involved in many developmental processes. It contains a MH domain and a TALE-class homeodomain (HD). It binds to another homeodomain Exd via its MH domain to promote the nuclear import of the Hth-Exd complex and serve as a cofactor for Hox proteins. The MH and HD domains in Hth as well as the HTh-Exd interaction are highly conserved in evolution. The alternatively spliced micro-exon lies between the exons encoding the MH and HD domains. We provide clear proof that the micro-Ex8 is produced by alternative splicing from a 48 bp full-length exon 8 (FL-Ex8) and the micro-Ex8 is the first three nt is FL-Ex8. We found that the micro-Ex8 is the ancient form and the 3 + 48 organization of alternatively spliced overlapping exons only emerged in the Schizophora group of Diptera and is absolutely conserved in this group. We then used several strategies to test the in vivo function of the two types of isoforms and found that the micro-Ex8 and FL-Ex8 isoforms have largely overlapping functions but also have non-redundant functions that are tissue-specific, which supports their strong evolutionary conservation. Since the different combinations of protein interaction of Hth with Exd and/or Hox can have different DNA target specificity, our finding of alternatively spliced isoforms adds to the spectrum of structural and functional diversity under developmental regulation.
MeSH term(s)	Alternative Splicing/genetics ; Animals ; Drosophila/genetics ; Drosophila Proteins/genetics ; Drosophila Proteins/physiology ; Evolution, Molecular ; Exons/genetics ; Gene Expression Regulation, Developmental/genetics ; Genes, Insect/genetics ; Homeodomain Proteins/genetics ; Homeodomain Proteins/physiology ; Protein Isoforms ; RNA Splice Sites/genetics
Chemical Substances	Drosophila Proteins ; Homeodomain Proteins ; Protein Isoforms ; RNA Splice Sites ; hth protein, Drosophila
Language	English
Publishing date	2020-07-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-69644-1
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Article ; Online: Temporal and spatial order of photoreceptor and glia projections into optic lobe in Drosophila.

Chang, Yen-Ching / Tsao, Chia-Kang / Sun, Y Henry

Scientific reports

2018 Volume 8, Issue 1, Page(s) 12669

Abstract: Photoreceptor (PR) axons project from the retina to the optic lobe in brain and form a precise retinotopic map in the Drosophila visual system. Yet the role of retinal basal glia in the retinotopic map formation is not previously known. We examined the ... ...

Abstract	Photoreceptor (PR) axons project from the retina to the optic lobe in brain and form a precise retinotopic map in the Drosophila visual system. Yet the role of retinal basal glia in the retinotopic map formation is not previously known. We examined the formation of the retinotopic map by marking single PR pairs and following their axonal projections. In addition to confirming previous studies that the spatial information is preserved from the retina to the optic stalk and then to the optic lamina, we found that the young PR R3/4 axons transiently overshoot and then retract to their final destination, the lamina plexus. We then examined the process of wrapping glia (WG) membrane extension in the eye disc and showed that the WG membrane extensions also follow the retinotopic map. We show that the WG is important for the proper spatial distribution of PR axons in the optic stalk and lamina, suggesting an active role of wrapping glia in the retinotopic map formation.
MeSH term(s)	Animals ; Axons/ultrastructure ; Drosophila melanogaster/physiology ; Drosophila melanogaster/ultrastructure ; Microscopy, Confocal/methods ; Microscopy, Electron, Transmission/methods ; Neuroglia/physiology ; Neuroglia/ultrastructure ; Optic Disk/ultrastructure ; Optic Lobe, Nonmammalian/ultrastructure ; Photoreceptor Cells, Invertebrate/cytology ; Photoreceptor Cells, Invertebrate/ultrastructure
Language	English
Publishing date	2018-08-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-30415-8
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Article ; Online: Maintenance of glia in the optic lamina is mediated by EGFR signaling by photoreceptors in adult Drosophila.

Lee, Yuan-Ming / Sun, Y Henry

PLoS genetics

2015 Volume 11, Issue 4, Page(s) e1005187

Abstract: The late onset of neurodegeneration in humans indicates that the survival and function of cells in the nervous system must be maintained throughout adulthood. In the optic lamina of the adult Drosophila, the photoreceptor axons are surrounded by multiple ...

Abstract	The late onset of neurodegeneration in humans indicates that the survival and function of cells in the nervous system must be maintained throughout adulthood. In the optic lamina of the adult Drosophila, the photoreceptor axons are surrounded by multiple types of glia. We demonstrated that the adult photoreceptors actively contribute to glia maintenance in their target field within the optic lamina. This effect is dependent on the epidermal growth factor receptor (EGFR) ligands produced by the R1-6 photoreceptors and transported to the optic lamina to act on EGFR in the lamina glia. EGFR signaling is necessary and sufficient to act in a cell-autonomous manner in the lamina glia. Our results suggest that EGFR signaling is required for the trafficking of the autophagosome/endosome to the lysosome. The loss of EGFR signaling results in cell degeneration most likely because of the accumulation of autophagosomes. Our findings provide in vivo evidence for the role of adult neurons in the maintenance of glia and a novel role for EGFR signaling in the autophagic flux.
MeSH term(s)	Animals ; Axons/metabolism ; Cell Differentiation/genetics ; Drosophila/growth & development ; Drosophila/metabolism ; ErbB Receptors/genetics ; Humans ; Neuroglia/metabolism ; Neurons/metabolism ; Photoreceptor Cells, Invertebrate/metabolism ; Retina/metabolism ; Retina/pathology ; Signal Transduction ; Spinal Cord Dorsal Horn/growth & development ; Spinal Cord Dorsal Horn/metabolism
Chemical Substances	ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2015-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1005187
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Article ; Online: Drosophila as a model to study the role of glia in neurodegeneration.

Lee, Yuan-Ming / Sun, Y Henry

Journal of neurogenetics

2015 Volume 29, Issue 2-3, Page(s) 69–79

Abstract: Neurons and glia interact reciprocally. Glia perform many important functions in the development and proper functioning of the nervous system throughout different stages of life. Neurons also affect the development and function of glia. Neurodegenerative ...

Abstract	Neurons and glia interact reciprocally. Glia perform many important functions in the development and proper functioning of the nervous system throughout different stages of life. Neurons also affect the development and function of glia. Neurodegenerative diseases are usually late-onset, progressive, and affect specific parts of the nervous system. Many neurodegenerative disorders have been extensively studied. However, the majority of the studies have focused on the events that occur in neurons. The events that occur in glia, and whether and how glia participate in the pathogenesis of these diseases, have not been as well studied. In this review, we will focus on how the fruit fly Drosophila melanogaster has been used as a model to study neuron-glia interactions in neurodegenerative disorders. We discuss how glia are affected in these models of human neurodegenerative disorders and how glia contribute to their pathogenesis. These studies have provided important insight into the mechanisms of diverse neurodegenerative disorders, and have suggested possibilities for early diagnosis.
MeSH term(s)	Animals ; Disease Models, Animal ; Drosophila ; Nerve Degeneration/pathology ; Neurodegenerative Diseases/pathology ; Neuroglia/pathology ; Neurons/pathology
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605543-6
ISSN	1563-5260 ; 0167-7063
ISSN (online)	1563-5260
ISSN	0167-7063
DOI	10.3109/01677063.2015.1076816
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Article ; Online: Long-term Live Imaging of Drosophila Eye Disc.

Tsao, Chia-Kang / Ku, Hui-Yu / Sun, Y Henry

Journal of visualized experiments : JoVE

2017 , Issue 123

Abstract: Live imaging provides the ability to continuously track dynamic cellular and developmental processes in real time. Drosophila larval imaginal discs have been used to study many biological processes, such as cell proliferation, differentiation, growth, ... ...

Abstract	Live imaging provides the ability to continuously track dynamic cellular and developmental processes in real time. Drosophila larval imaginal discs have been used to study many biological processes, such as cell proliferation, differentiation, growth, migration, apoptosis, competition, cell-cell signaling, and compartmental boundary formation. However, methods for the long-term ex vivo culture and live imaging of the imaginal discs have not been satisfactory, despite many efforts. Recently, we developed a method for the long-term ex vivo culture and live imaging of imaginal discs for up to 18 h. In addition to using a high insulin concentration in the culture medium, a low-melting agarose was also used to embed the disc to prevent it from drifting during the imaging period. This report uses the eye-antennal discs as an example. Photoreceptor R3/4-specific mδ0.5-Ga4 expression was followed to demonstrate that photoreceptor differentiation and ommatidial rotation can be observed during a 10 h live imaging period. This is a detailed protocol describing this simple method.
Language	English
Publishing date	2017-05-06
Publishing country	United States
Document type	Journal Article
ISSN	1940-087X
ISSN (online)	1940-087X
DOI	10.3791/55748
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Article ; Online: Segregation of eye and antenna fates maintained by mutual antagonism in Drosophila.

Wang, Cheng-Wei / Sun, Y Henry

Development (Cambridge, England)

2012 Volume 139, Issue 18, Page(s) 3413–3421

Abstract: A general question in development is how do adjacent primordia adopt different developmental fates and stably maintain their distinct fates? In Drosophila melanogaster, the adult eye and antenna originate from the embryonic eye-antenna primordium. These ... ...

Abstract	A general question in development is how do adjacent primordia adopt different developmental fates and stably maintain their distinct fates? In Drosophila melanogaster, the adult eye and antenna originate from the embryonic eye-antenna primordium. These cells proliferate in the larval stage to form the eye-antenna disc. The eye or antenna differs at mid second instar with the restricted expression of Cut (Ct), a homeodomain transcriptional repressor, in the antenna disc and Eyeless (Ey), a Pax6 transcriptional activator, in the eye disc. In this study, we show that ey transcription in the antenna disc is repressed by two homeodomain proteins, Ct and Homothorax (Hth). Loss of Ct and Hth in the antenna disc resulted in ectopic eye development in the antenna. Conversely, the Ct and Hth expression in the eye disc was suppressed by the homeodomain transcription factor Sine oculis (So), a direct target of Ey. Loss of So in the eye disc caused ectopic antenna development in the eye. Therefore, the segregation of eye and antenna fates is stably maintained by mutual repression of the other pathway.
MeSH term(s)	Animals ; Arthropod Antennae/embryology ; Arthropod Antennae/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/embryology ; Drosophila melanogaster/metabolism ; Eye/embryology ; Eye/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; Drosophila Proteins ; Homeodomain Proteins ; Nuclear Proteins ; Transcription Factors ; ct protein, Drosophila ; ey protein, Drosophila ; hth protein, Drosophila
Language	English
Publishing date	2012-08-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.078857
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Article ; Online: Introduction to special issue on retinal development.

Feller, Marla B / Sun, Y Henry

Developmental neurobiology

2011 Volume 71, Issue 12, Page(s) 1131–1132

MeSH term(s)	Animals ; Humans ; Retina/cytology ; Retina/growth & development
Language	English
Publishing date	2011-12
Publishing country	United States
Document type	Editorial
ZDB-ID	2256184-5
ISSN	1932-846X ; 1097-4695 ; 1932-8451 ; 0022-3034
ISSN (online)	1932-846X ; 1097-4695
ISSN	1932-8451 ; 0022-3034
DOI	10.1002/dneu.20952
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