Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish
The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-di...
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| Veröffentlicht in: | Development (Cambridge) 2017-07, Vol.144 (14), p.2595-2605 |
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| creator | Dimri, Manali Bilogan, Cassandra Pierce, Lain X Naegele, Gregory Vasanji, Amit Gibson, Isabel McClendon, Allyson Tae, Kevin Sakaguchi, Takuya F |
| description | The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in
(
), an essential activator of Cdk5.
mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network. |
| doi_str_mv | 10.1242/dev.147397 |
| format | Article |
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(
), an essential activator of Cdk5.
mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.147397</identifier><identifier>PMID: 28720653</identifier><language>eng</language><publisher>England: The Company of Biologists Ltd</publisher><subject>Actin ; Actin Depolymerizing Factors - metabolism ; Algorithms ; Animals ; Animals, Genetically Modified ; Bile Ducts, Intrahepatic - enzymology ; Bile Ducts, Intrahepatic - growth & development ; Computer Simulation ; Cyclin-dependent kinase 5 ; Cyclin-Dependent Kinase 5 - antagonists & inhibitors ; Cyclin-Dependent Kinase 5 - genetics ; Cyclin-Dependent Kinase 5 - metabolism ; Cyclin-dependent kinases ; Danio rerio ; Epithelial cells ; Gene Knockout Techniques ; Imaging, Three-Dimensional ; Larva - growth & development ; Larva - metabolism ; Lim Kinases - metabolism ; Liver ; Models, Anatomic ; Morphogenesis ; Morphogenesis - drug effects ; Morphogenesis - genetics ; Morphogenesis - physiology ; Mutation ; p21-Activated Kinases - metabolism ; Protein Kinase Inhibitors - pharmacology ; Signal Transduction ; Zebrafish - genetics ; Zebrafish - growth & development ; Zebrafish - metabolism ; Zebrafish Proteins - antagonists & inhibitors ; Zebrafish Proteins - genetics ; Zebrafish Proteins - metabolism</subject><ispartof>Development (Cambridge), 2017-07, Vol.144 (14), p.2595-2605</ispartof><rights>2017. Published by The Company of Biologists Ltd.</rights><rights>Copyright The Company of Biologists Ltd Jul 15, 2017</rights><rights>2017. Published by The Company of Biologists Ltd 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-21ae23bb27c7a68582e813f78c5bd6f20b79f683ec0cd51add1a0696e91abf443</citedby><cites>FETCH-LOGICAL-c476t-21ae23bb27c7a68582e813f78c5bd6f20b79f683ec0cd51add1a0696e91abf443</cites><orcidid>0000-0002-8422-0902 ; 0000-0002-7161-5462</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3665,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28720653$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dimri, Manali</creatorcontrib><creatorcontrib>Bilogan, Cassandra</creatorcontrib><creatorcontrib>Pierce, Lain X</creatorcontrib><creatorcontrib>Naegele, Gregory</creatorcontrib><creatorcontrib>Vasanji, Amit</creatorcontrib><creatorcontrib>Gibson, Isabel</creatorcontrib><creatorcontrib>McClendon, Allyson</creatorcontrib><creatorcontrib>Tae, Kevin</creatorcontrib><creatorcontrib>Sakaguchi, Takuya F</creatorcontrib><title>Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish</title><title>Development (Cambridge)</title><addtitle>Development</addtitle><description>The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in
(
), an essential activator of Cdk5.
mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network.</description><subject>Actin</subject><subject>Actin Depolymerizing Factors - metabolism</subject><subject>Algorithms</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Bile Ducts, Intrahepatic - enzymology</subject><subject>Bile Ducts, Intrahepatic - growth & development</subject><subject>Computer Simulation</subject><subject>Cyclin-dependent kinase 5</subject><subject>Cyclin-Dependent Kinase 5 - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinase 5 - genetics</subject><subject>Cyclin-Dependent Kinase 5 - metabolism</subject><subject>Cyclin-dependent kinases</subject><subject>Danio rerio</subject><subject>Epithelial cells</subject><subject>Gene Knockout Techniques</subject><subject>Imaging, Three-Dimensional</subject><subject>Larva - growth & development</subject><subject>Larva - metabolism</subject><subject>Lim Kinases - metabolism</subject><subject>Liver</subject><subject>Models, Anatomic</subject><subject>Morphogenesis</subject><subject>Morphogenesis - drug effects</subject><subject>Morphogenesis - genetics</subject><subject>Morphogenesis - physiology</subject><subject>Mutation</subject><subject>p21-Activated Kinases - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Signal Transduction</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish - growth & development</subject><subject>Zebrafish - metabolism</subject><subject>Zebrafish Proteins - antagonists & inhibitors</subject><subject>Zebrafish Proteins - genetics</subject><subject>Zebrafish Proteins - metabolism</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2KFDEUhYMoTju68QEk4EYGasxP5W8jDI2jwoCbcR1Sya2uTFen2qSqZXwAn9s0PQ7qKueSj8O59yD0mpJLylr2PsDhkraKG_UErapQjaHMPEUrYgRpqDH0DL0o5Y4QwqVSz9EZ04oRKfgK_bodMkAT4g5SiVNyIy5zXvy85Cpdne9LLDjDAdxYsMPrsBXNDkJ0MwS8jckVwN4V7wJUbLOMbo5pgwfYV-FxF8fo8j1OMP-Y8hZ32SU_HImY8E-oYx_L8BI966s_vHp4z9G364-368_NzddPX9ZXN41vlZwbRh0w3nVMeeWkFpqBprxX2osuyJ6RTpleag6e-CCoC4E6Io0EQ13Xty0_Rx9Ovvulq0t4SHPd0-5z3NWQdnLR_vuT4mA308EKwaVhohq8ezDI0_cFymx3sXgYR5dgWoqlhhFumFGyom__Q--mJdeLHinNW6pNqyt1caJ8nkrJ0D-GocQe67W1Xnuqt8Jv_o7_iP7pk_8GEbukcA</recordid><startdate>20170715</startdate><enddate>20170715</enddate><creator>Dimri, Manali</creator><creator>Bilogan, Cassandra</creator><creator>Pierce, Lain X</creator><creator>Naegele, Gregory</creator><creator>Vasanji, Amit</creator><creator>Gibson, Isabel</creator><creator>McClendon, Allyson</creator><creator>Tae, Kevin</creator><creator>Sakaguchi, Takuya F</creator><general>The Company of Biologists Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8422-0902</orcidid><orcidid>https://orcid.org/0000-0002-7161-5462</orcidid></search><sort><creationdate>20170715</creationdate><title>Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish</title><author>Dimri, Manali ; Bilogan, Cassandra ; Pierce, Lain X ; Naegele, Gregory ; Vasanji, Amit ; Gibson, Isabel ; McClendon, Allyson ; Tae, Kevin ; Sakaguchi, Takuya F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-21ae23bb27c7a68582e813f78c5bd6f20b79f683ec0cd51add1a0696e91abf443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Actin</topic><topic>Actin Depolymerizing Factors - metabolism</topic><topic>Algorithms</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Bile Ducts, Intrahepatic - enzymology</topic><topic>Bile Ducts, Intrahepatic - growth & development</topic><topic>Computer Simulation</topic><topic>Cyclin-dependent kinase 5</topic><topic>Cyclin-Dependent Kinase 5 - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinase 5 - genetics</topic><topic>Cyclin-Dependent Kinase 5 - metabolism</topic><topic>Cyclin-dependent kinases</topic><topic>Danio rerio</topic><topic>Epithelial cells</topic><topic>Gene Knockout Techniques</topic><topic>Imaging, Three-Dimensional</topic><topic>Larva - growth & development</topic><topic>Larva - metabolism</topic><topic>Lim Kinases - metabolism</topic><topic>Liver</topic><topic>Models, Anatomic</topic><topic>Morphogenesis</topic><topic>Morphogenesis - drug effects</topic><topic>Morphogenesis - genetics</topic><topic>Morphogenesis - physiology</topic><topic>Mutation</topic><topic>p21-Activated Kinases - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Signal Transduction</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish - growth & development</topic><topic>Zebrafish - metabolism</topic><topic>Zebrafish Proteins - antagonists & inhibitors</topic><topic>Zebrafish Proteins - genetics</topic><topic>Zebrafish Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dimri, Manali</creatorcontrib><creatorcontrib>Bilogan, Cassandra</creatorcontrib><creatorcontrib>Pierce, Lain X</creatorcontrib><creatorcontrib>Naegele, Gregory</creatorcontrib><creatorcontrib>Vasanji, Amit</creatorcontrib><creatorcontrib>Gibson, Isabel</creatorcontrib><creatorcontrib>McClendon, Allyson</creatorcontrib><creatorcontrib>Tae, Kevin</creatorcontrib><creatorcontrib>Sakaguchi, Takuya F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Development (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dimri, Manali</au><au>Bilogan, Cassandra</au><au>Pierce, Lain X</au><au>Naegele, Gregory</au><au>Vasanji, Amit</au><au>Gibson, Isabel</au><au>McClendon, Allyson</au><au>Tae, Kevin</au><au>Sakaguchi, Takuya F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2017-07-15</date><risdate>2017</risdate><volume>144</volume><issue>14</issue><spage>2595</spage><epage>2605</epage><pages>2595-2605</pages><issn>0950-1991</issn><eissn>1477-9129</eissn><abstract>The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in
(
), an essential activator of Cdk5.
mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network.</abstract><cop>England</cop><pub>The Company of Biologists Ltd</pub><pmid>28720653</pmid><doi>10.1242/dev.147397</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-8422-0902</orcidid><orcidid>https://orcid.org/0000-0002-7161-5462</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-1991 |
| ispartof | Development (Cambridge), 2017-07, Vol.144 (14), p.2595-2605 |
| issn | 0950-1991 1477-9129 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Company of Biologists |
| subjects | Actin Actin Depolymerizing Factors - metabolism Algorithms Animals Animals, Genetically Modified Bile Ducts, Intrahepatic - enzymology Bile Ducts, Intrahepatic - growth & development Computer Simulation Cyclin-dependent kinase 5 Cyclin-Dependent Kinase 5 - antagonists & inhibitors Cyclin-Dependent Kinase 5 - genetics Cyclin-Dependent Kinase 5 - metabolism Cyclin-dependent kinases Danio rerio Epithelial cells Gene Knockout Techniques Imaging, Three-Dimensional Larva - growth & development Larva - metabolism Lim Kinases - metabolism Liver Models, Anatomic Morphogenesis Morphogenesis - drug effects Morphogenesis - genetics Morphogenesis - physiology Mutation p21-Activated Kinases - metabolism Protein Kinase Inhibitors - pharmacology Signal Transduction Zebrafish - genetics Zebrafish - growth & development Zebrafish - metabolism Zebrafish Proteins - antagonists & inhibitors Zebrafish Proteins - genetics Zebrafish Proteins - metabolism |
| title | Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish |
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