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Dive into the research topics where Pao-Tien Chuang is active.

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Featured researches published by Pao-Tien Chuang.


Nature | 1999

Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein

Pao-Tien Chuang; Andrew P. McMahon

The Hedgehog signalling pathway is essential for the development of diverse tissues during embryogenesis. Signalling is activated by binding of Hedgehog protein to the multipass membrane protein Patched (Ptc). We have now identified a novel component in the vertebrate signalling pathway, which we name Hip (for Hedgehog-interacting protein) because of its ability to bind Hedgehog proteins. Hip encodes a membrane glycoprotein that binds to all three mammalian Hedgehog proteins with an affinity comparable to that of Ptc-1. Hip-expressing cells are located next to cells that express each Hedgehog gene. Hip expression is induced by ectopic Hedgehog signalling and is lost in Hedgehog mutants. Thus, Hip, like Ptc-1, is a general transcriptional target of Hedgehog signalling. Overexpression of Hip in cartilage, where Indian hedgehog (Ihh) controls growth, leads to a shortened skeleton that resembles that seen when Ihh function is lost (B. St-Jacques, M. Hammerschmidt & A.P.M., in preparation). Our findings support a model in which Hip attenuates Hedgehog signalling as a result of binding to Hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any Hedgehog signal.


Genes & Development | 2009

Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved

Miao-Hsueh Chen; Christopher W. Wilson; Ya-Jun Li; Kelvin King Lo Law; Chi-Sheng Lu; Rhodora Gacayan; Xiaoyun Zhang; Chi-chung Hui; Pao-Tien Chuang

A central question in Hedgehog (Hh) signaling is how evolutionarily conserved components of the pathway might use the primary cilium in mammals but not fly. We focus on Suppressor of fused (Sufu), a major Hh regulator in mammals, and reveal that Sufu controls protein levels of full-length Gli transcription factors, thus affecting the production of Gli activators and repressors essential for graded Hh responses. Surprisingly, despite ciliary localization of most Hh pathway components, regulation of Gli protein levels by Sufu is cilium-independent. We propose that Sufu-dependent processes in Hh signaling are evolutionarily conserved. Consistent with this, Sufu regulates Gli protein levels by antagonizing the activity of Spop, a conserved Gli-degrading factor. Furthermore, addition of zebrafish or fly Sufu restores Gli protein function in Sufu-deficient mammalian cells. In contrast, fly Smo is unable to translocate to the primary cilium and activate the mammalian Hh pathway. We also uncover a novel positive role of Sufu in regulating Hh signaling, resulting from its control of both Gli activator and repressor function. Taken together, these studies delineate important aspects of cilium-dependent and cilium-independent Hh signal transduction and provide significant mechanistic insight into Hh signaling in diverse species.


Nucleic Acids Research | 2003

BayGenomics: a resource of insertional mutations in mouse embryonic stem cells

Doug Stryke; Michiko Kawamoto; Conrad C. Huang; Susan J. Johns; Leslie A. King; Courtney A. Harper; Elaine C. Meng; Roy E. Lee; Alice Yee; Larry L'Italien; Pao-Tien Chuang; Stephen G. Young; William C. Skarnes; Patricia C. Babbitt; Thomas E. Ferrin

The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.


Cell | 1994

DPY-27: A chromosome condensation protein homolog that regulates C. elegans dosage compensation through association with the X chromosome

Pao-Tien Chuang; Donna G. Albertson; Barbara J Meyer

dpy-27 is an essential dosage compensation gene that acts to reduce expression of both hermaphrodite X chromosomes. The DPY-27 protein becomes specifically localized to the X chromosomes of wild-type XX embryos, but remains diffusely distributed throughout the nuclei of male (XO) embryos. In xol-1 mutant XO embryos that activate the XX mode of dosage compensation and die from inappropriately low X chromosome transcript levels, DPY-27 becomes localized to X. Therefore, sex specificity of the dosage compensation process is regulated at the step of DPY-27 X chromosome localization. DPY-27 exhibits striking similarity to proteins required for assembly and structural maintenance of Xenopus chromosomes in vitro and for segregation of yeast chromosomes in vivo. These findings suggest a link between global regulation of gene expression and higher order chromosome structure. We propose that DPY-27 implements dosage compensation by condensing the chromatin structure of X in a manner that causes general reduction of X chromosome expression.


Science | 1996

Sex-Specific Assembly of a Dosage Compensation Complex on the Nematode X Chromosome

Pao-Tien Chuang; Jason D. Lieb; Barbara J Meyer

In nematodes, flies, and mammals, dosage compensation equalizes X-chromosome gene expression between the sexes through chromosome-wide regulatory mechanisms that function in one sex to adjust the levels of X-linked transcripts. Here, a dosage compensation complex was identified in the nematode Caenorhabditis elegans that reduces transcript levels from the two X chromosomes in hermaphrodites. This complex contains at least four proteins, including products of the dosage compensation genes dpy-26 and dpy-27. Specific localization of the complex to the hermaphrodite X chromosomes is conferred by XX-specific regulatory genes that coordinately control both sex determination and dosage compensation.


Development | 2008

Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy

Kinglun Kingston Mak; Henry M. Kronenberg; Pao-Tien Chuang; Susan Mackem; Yingzi Yang

Chondrocyte hypertrophy is an essential process required for endochondral bone formation. Proper regulation of chondrocyte hypertrophy is also required in postnatal cartilage homeostasis. Indian hedgehog (Ihh) and PTHrP signaling play crucial roles in regulating the onset of chondrocyte hypertrophy by forming a negative feedback loop, in which Ihh signaling regulates chondrocyte hypertrophy by controlling PTHrP expression. To understand whether there is a PTHrP-independent role of Ihh signaling in regulating chondrocyte hypertrophy, we have both activated and inactivated Ihh signaling in the absence of PTHrP during endochondral skeletal development. We found that upregulating Ihh signaling in the developing cartilage by treating PTHrP-/- limb explants with sonic hedgehog (Shh) protein in vitro, or overexpressing Ihh in the cartilage of PTHrP-/- embryos or inactivating patched 1 (Ptch1), a negative regulator of hedgehog (Hh) signaling, accelerated chondrocyte hypertrophy in the PTHrP-/- embryos. Conversely, when Hh signaling was blocked by cyclopamine or by removing Smoothened (Smo), a positive regulator of Hh signaling, chondrocyte hypertrophy was delayed in the PTHrP-/- embryo. Furthermore, we show that upregulated Hh signaling in the postnatal cartilage led to accelerated chondrocyte hypertrophy during secondary ossification, which in turn caused reduction of joint cartilage. Our results revealed a novel role of Ihh signaling in promoting chondrocyte hypertrophy independently of PTHrP, which is particularly important in postnatal cartilage development and homeostasis. In addition, we found that bone morphogenetic protein (Bmp) and Wnt/β-catenin signaling in the cartilage may both mediate the effect of upregulated Ihh signaling in promoting chondrocyte hypertrophy.


Cell | 1998

MIX-1 : AN ESSENTIAL COMPONENT OF THE C. ELEGANS MITOTIC MACHINERY EXECUTES X CHROMOSOME DOSAGE COMPENSATION

Jason D. Lieb; Michael R. Albrecht; Pao-Tien Chuang; Barbara J Meyer

We show that a functional component of the C. elegans mitotic machinery regulates X chromosome gene expression. This protein, MIX-1, is a member of the dosage compensation complex that associates specifically with hermaphrodite X chromosomes to reduce their gene expression during interphase. MIX-1 also associates with all mitotic chromosomes to ensure their proper segregation. Both dosage compensation and mitosis are severely disrupted by mix-1 mutations. MIX-1 belongs to the SMC protein family required for mitotic chromosome condensation and segregation in yeast and frogs. Thus, an essential, conserved component of mitotic chromosomes has been recruited to the dosage compensation process. Rather than dosage compensation and mitosis being achieved by two separate sets of related genes, these two processes share an identical component, indicating a common mechanism for establishing higher order chromosome structure and proper X chromosome gene expression.


Development | 2006

GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis

Ming Chang Hu; Rong Mo; Sita Bhella; Christopher W. Wilson; Pao-Tien Chuang; Chi Chung Hui; Norman D. Rosenblum

Truncating mutations in Gli3, an intracellular effector in the SHH-SMO-GLI signaling pathway, cause renal aplasia/dysplasia in humans and mice. Yet, the pathogenic mechanisms are undefined. Here, we report the effect of decreased SHH-SMO signaling on renal morphogenesis, the expression of SHH target genes and GLI binding to Shh target genes. Shh deficiency or cyclopamine-mediated SMO inhibition disrupted renal organogenesis, decreased expression of GLI1 and GLI2 proteins, but increased expression of GLI3 repressor relative to GLI3 activator. Shh deficiency decreased expression of kidney patterning genes (Pax2 and Sall1) and cell cycle regulators (cyclin D1 and MYCN). Elimination of Gli3 in Shh–/– mice rescued kidney malformation and restored expression of Pax2, Sall1, cyclin D1, MYCN, Gli1 and Gli2. To define mechanisms by which SHH-SMO signaling controls gene expression, we determined the binding of GLI proteins to 5′ flanking regions containing GLI consensus binding sequences in Shh target genes using chromatin immunoprecipitation. In normal embryonic kidney tissue, GLI1 and/or GLI2 were bound to each target gene. By contrast, treatment of embryonic kidney explants with cyclopamine decreased GLI1 and/or GLI2 binding, and induced binding of GLI3. However, cyclopamine failed to decrease Gli1 and Gli2 expression and branching morphogenesis in Gli3-deficient embryonic kidney tissue. Together, these results demonstrate that SHH-SMO signaling controls renal morphogenesis via transcriptional control of Gli, renal patterning and cell cycle regulator genes in a manner that is opposed by GLI3.


Development | 2006

Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation

Kingston Kinglun Mak; Miao-Hsueh Chen; Timothy F. Day; Pao-Tien Chuang; Yingzi Yang

Both the Wnt/β-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated theβ -catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using β-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/β-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. β-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, β-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently ofβ -catenin. However, there is a strong synergistic interaction between Wnt/β-catenin and Ihh signaling in regulating synovial joint formation.


Development | 2002

Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling

Takatoshi Kawakami; T'Nay Kawcak; Ya-Jun Li; Wanhui Zhang; Yongmei Hu; Pao-Tien Chuang

Hedgehog (Hh) signaling plays a major role in multiple aspects of embryonic development, which involves both short- and long-range signaling from localized Hh sources. One unusual aspect of Hh signaling is the autoproteolytic processing of Hh followed by lipid modification. As a consequence, the N-terminal fragment of Hh becomes membrane anchored on the cell surface of Hh-producing cells. A key issue in Hh signaling is to understand the molecular mechanisms by which lipid-modified Hh protein is transported from its sites of synthesis and subsequently moves through the morphogenetic field. The dispatched gene, which encodes a putative multipass membrane protein, was initially identified in Drosophila and is required in Hh-producing cells, where it facilitates the transport of cholesterol-modified Hh. We report the identification of the mouse dispatched (Disp) gene and a phenotypic analysis of Disp mutant mice. Disp-null mice phenocopy mice deficient in the smoothened gene, an essential component for Hh reception, suggesting that Disp is essential for Hh signaling. This conclusion was further supported by a detailed molecular analysis of Disp knockout mice, which exhibit defects characteristic of loss of Hh signaling. We also provide evidence that Disp is not required for Hh protein synthesis or processing, but rather for the movement of Hh protein from its sites of synthesis in mice. Taken together, our results reveal a conserved mechanism of Hh protein movement in Hh-producing cells that is essential for proper Hh signaling.

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Andrew P. McMahon

University of Southern California

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Chuwen Lin

University of California

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Erica Yao

University of California

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Hai Song

National Institutes of Health

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Ya-Jun Li

University of California

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