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The Zic family homologue Odd-paired regulates Alk expression in Drosophila
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2017 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 4, artikel-id e1006617Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.

Ort, förlag, år, upplaga, sidor
PUBLIC LIBRARY SCIENCE , 2017. Vol. 13, nr 4, artikel-id e1006617
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-137009DOI: 10.1371/journal.pgen.1006617ISI: 000402549200004OAI: oai:DiVA.org:umu-137009DiVA, id: diva2:1117723
Tillgänglig från: 2017-06-29 Skapad: 2017-06-29 Senast uppdaterad: 2019-09-18Bibliografiskt granskad
Ingår i avhandling
1. Harnessing the power of model systems to investigate regulation of Anaplastic Lymphoma Kinase function
Öppna denna publikation i ny flik eller fönster >>Harnessing the power of model systems to investigate regulation of Anaplastic Lymphoma Kinase function
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The anaplastic lymphoma kinase (ALK), initially identified as a translocation partner in anaplastic large cell lymphoma (ALCL), has been described in a number of tumors such as neuroblastoma. Neuroblastoma is a neural crest derived malignancy of the sympathetic nervous system. Therefore, understanding regulation of ALK transcription and activity in the context of normal neural crest development might highlight abnormal events contributing to neuroblastoma initiation. The use of vertebrate model systems has been very important for studying in detail the pathways activated during neural crest development, their contribution to neuroblastoma and the identification of therapeutic targets.

Using a yeast one-hybrid approach, we identified Odd-paired (Opa) as a potential transcription factor modulating Alk expression in the Drosophila visceral mesoderm (VM) (Paper I). Opa promotes Alk expression in the VM in combination with Bagpipe (Bap) and Biniou (Bin) through binding to the here identified AlkEB9 enhancer region.

In a subsequent paper, we identified ALKAL1 and ALKAL2 as the activating ligands for the human ALK (Paper II). Using a combination of in vitro and cell culture assays we show that the ALKAL proteins can bind and activate human ALK. Moreover, ALKAL proteins can “super-activate” mutant ALK, highlighting a putative role for the ALKALs/ALK axis in neuroblastoma.

The third paper shows in vivo evidence of ALKAL activity during zebrafish neural crest development (Paper III). We identified and characterized three zebrafish Alkal proteins and demonstrated their ability to activate human and zebrafish ALK family RTKs. Zebrafish Alkals activate the ALK-related receptor leukocyte tyrosine kinase (LTK) in the neural crest to promote iridophore development.

In the last paper, we employed the DamID approach on the Drosophila VM and identified the transcription factor Kahuli (Kah) as an Alk transcriptional target in this tissue (Paper IV). We also addressed the in vivo iv Kah role during embryogenesis and showed that Kah is required for normal midgut invaginations and formation of the body wall musculature.

Together, this thesis highlights the importance of ALK receptor signaling during development in vertebrate and invertebrate models. Further, it shows that ALKAL signaling via the activation of the ALK family receptors are involved in neural crest development.

Ort, förlag, år, upplaga, sidor
Umea: Academic Publications, 2019. s. 69
Nyckelord
RTK, ALK, Drosophila, Danio rerio, ALKALs, signal transduction, transcription factor, visceral mesoderm, iridophores, neural crest
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-163395 (URN)978-91-7855-095-1 (ISBN)
Disputation
2019-10-11, Europa hörsalen, Conference Center Wallenberg, Medicinaregatan 20, Gothenburg, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

I publikationen felaktigt angivet att avhandlingen ingår i serien Umeå University medical dissertations, ISSN 0346-6612. 

Tillgänglig från: 2019-09-20 Skapad: 2019-09-18 Senast uppdaterad: 2019-09-24Bibliografiskt granskad

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