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dc.contributor.advisorDr. Charles G. Sagerstrom
dc.contributor.authorChoe, Seong-Kyu
dc.date2022-08-11T08:08:44.000
dc.date.accessioned2022-08-23T16:06:24Z
dc.date.available2022-08-23T16:06:24Z
dc.date.issued2003-12-11
dc.date.submitted2006-06-02
dc.identifier.doi10.13028/ke58-mt40
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32056
dc.description.abstractHindbrain patterning requires many factors involved in early segmentation and later segment identity of the specific domains of the hindbrain. Hox proteins and their cofactors are of great importance during segmentation of the hindbrain, because segmentation and/or segment identity are lost when any of them are lost. Previously, we have reported that Meis proteins synergize with Pbx, another Hox cofactor, and Hox proteins expressed in the hindbrain. To further investigate Meis function during hindbrain development, we utilized a Meis dominant-negative molecule, ΔCPbx4, and expressed it in zebrafish embryos. We find that ΔCPbx4 affects gene expression and neuronal differentiation especially in r3 through r5. Further, we combined ΔCPbx4 with another Meis dominant-negative molecule (ΔHDCMeis) to disrupt Meis function more extensively. Under these conditions, we find that the entire hindbrain loses gene expression as well as its complement of neuronal differentiation. This phenotype is strikingly similar to that of loss of Pbx function, suggesting that Meis proteins act in the same pathway as Pbx. Therefore, Meis family proteins are indispensable for the entire hindbrain segmentation. In addition to the milder effect on hindbrain patterning, we also found upon expressing ΔCPbx4 that the caudal hindbrain transforms to r4-like fates, supported by expression of r4-specific marker gene (hoxbla) and specification of r4-specifc Mauthner neurons in the domain. This phenotype is not reported upon loss of Pbx function, suggesting that Meis proteins may play a more modulatory role, while Pbx is absolutely required during hindbrain development. Through several in vivo assays, we find that this r4 transformation is induced by Hox PG1 proteins and that vhnf1 represses r4 fates in the caudal hindbrain to further specify caudal fates in this region. Based on these results, we propose a model by which hindbrain patterning is achieved. Initially, un-segmented hindbrain is segmented into two domains wherein the caudal domain displays an r4 fate. This caudal r4 fate is then repressed by vhnf1 function which restricts the r4 fate to the presumptive r4 domain and specifies r5 and r6 by inducing its downstream genes such as valentino and hox PG3. Taken together, we conclude that Meis family proteins are essentially involved in function of Hox complexes to specify distinct rhombomeres during segmentation of the zebrafish hindbrain.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectZebrafish
dc.subjectRhombencephalon
dc.subjectGene Expression Regulation
dc.subjectDevelopmental
dc.subjectZebrafish Proteins
dc.subjectHomeodomain Proteins
dc.subjectHomeodomain Proteins
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectNervous System
dc.titleEssential Roles of the Meis Family Proteins During Segmentation of the Zebrafish Hindbrain : a Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1006&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/7
dc.legacy.embargo2017-04-24T00:00:00-07:00
dc.identifier.contextkey171062
refterms.dateFOA2022-08-26T04:30:51Z
html.description.abstract<p>Hindbrain patterning requires many factors involved in early segmentation and later segment identity of the specific domains of the hindbrain. Hox proteins and their cofactors are of great importance during segmentation of the hindbrain, because segmentation and/or segment identity are lost when any of them are lost. Previously, we have reported that Meis proteins synergize with Pbx, another Hox cofactor, and Hox proteins expressed in the hindbrain. To further investigate Meis function during hindbrain development, we utilized a Meis dominant-negative molecule, ΔCPbx4, and expressed it in zebrafish embryos. We find that ΔCPbx4 affects gene expression and neuronal differentiation especially in r3 through r5. Further, we combined ΔCPbx4 with another Meis dominant-negative molecule (ΔHDCMeis) to disrupt Meis function more extensively. Under these conditions, we find that the entire hindbrain loses gene expression as well as its complement of neuronal differentiation. This phenotype is strikingly similar to that of loss of Pbx function, suggesting that Meis proteins act in the same pathway as Pbx. Therefore, Meis family proteins are indispensable for the entire hindbrain segmentation. In addition to the milder effect on hindbrain patterning, we also found upon expressing ΔCPbx4 that the caudal hindbrain transforms to r4-like fates, supported by expression of r4-specific marker gene (<em>hoxbla</em>) and specification of r4-specifc Mauthner neurons in the domain. This phenotype is not reported upon loss of Pbx function, suggesting that Meis proteins may play a more modulatory role, while Pbx is absolutely required during hindbrain development. Through several in vivo assays, we find that this r4 transformation is induced by Hox PG1 proteins and that <em>vhnf1</em> represses r4 fates in the caudal hindbrain to further specify caudal fates in this region. Based on these results, we propose a model by which hindbrain patterning is achieved. Initially, un-segmented hindbrain is segmented into two domains wherein the caudal domain displays an r4 fate. This caudal r4 fate is then repressed by vhnf1 function which restricts the r4 fate to the presumptive r4 domain and specifies r5 and r6 by inducing its downstream genes such as <em>valentino</em> and <em>hox PG3</em>. Taken together, we conclude that Meis family proteins are essentially involved in function of Hox complexes to specify distinct rhombomeres during segmentation of the zebrafish hindbrain.</p>
dc.identifier.submissionpathgsbs_diss/7
dc.contributor.departmentBiochemistry and Molecular Pharmacology
dc.description.thesisprogramBiochemistry and Molecular Pharmacology


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