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Alternative LIM homeodomain splice variants are dynamically regulated at key developmental steps in vertebrates
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).ORCID-id: 0000-0003-0619-4777
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).ORCID-id: 0000-0002-1657-7985
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).ORCID-id: 0000-0002-7461-7236
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).ORCID-id: 0000-0002-9793-1631
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2022 (Engelska)Ingår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 251, nr 7, s. 1223-1243Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Alternative splicing provides a broad strategy to amplify the genome. Yet how alternative splicing influences neurodevelopment or indeed which variants are translated at developmental choice points remains poorly explored. Here we focused on a gene important for neurodevelopment, the Lim homeodomain transcription factor, Lhx9. Lhx9 has two noncanonical splice variants, Lhx9a and Lhx9b which compared with the canonical variant Lhx9c have a truncated homeodomain and an alternative C-terminal sequence, suggesting that, if translated, these variants could differently impact on cellular function.

Results: We created a unique antibody tool designed to selectively detect noncanonical Lhx9 variants (Lhx9ab) and used this to examine the protein expression dynamics in embryos. Lhx9ab variants were translated and dynamically expressed similarly between mouse and chicken at key developmental choice points in the spinal cord, limbs and urogenital ridge. Within the spinal cord, enrichment of Lhx9c vs Lhx9ab expression was observed during key migration and axonal projection choice points.

Conclusions: These data support the notion that the expression dynamics between canonical and noncanonical Lhx9 variants could play an important role in spinal neuron maturation. More broadly, determining the temporal dynamics of alternative protein variants is a key entry point to understand how splicing influences developmental processes.

Ort, förlag, år, upplaga, sidor
American Association for Anatomy , 2022. Vol. 251, nr 7, s. 1223-1243
Nyckelord [en]
axon guidance, chick, Lhx2, Lhx9, mouse, neurodevelopment, neuron, spinal cord, splice, transcription factor, urogenital ridge
Nationell ämneskategori
Utvecklingsbiologi Medicinsk genetik Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-193597DOI: 10.1002/dvdy.466ISI: 000770304200001PubMedID: 35247020Scopus ID: 2-s2.0-85126786373OAI: oai:DiVA.org:umu-193597DiVA, id: diva2:1651484
Forskningsfinansiär
Vetenskapsrådet, 2015‐05289Tillgänglig från: 2022-04-12 Skapad: 2022-04-12 Senast uppdaterad: 2023-11-20Bibliografiskt granskad
Ingår i avhandling
1. Molecular mechanisms of nerve-tumor interactions: the intersection of cancer and neurodevelopment
Öppna denna publikation i ny flik eller fönster >>Molecular mechanisms of nerve-tumor interactions: the intersection of cancer and neurodevelopment
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Molekylära mekanismer för interaktioner mellan nerver och tumörer : kopplingar mellan cancer och neuroutveckling
Abstract [en]

A wide range of cancers throughout the body are characterized by high nerve density and invasion of cancer cells within the nerves, a process called perineural invasion (PNI). Work in the field has shown that blocking nerves in organs with tumors leads to improved disease outcomes suggesting that finding ways to block tumor nerves could lead to new treatment approaches. Despite the importance of this, little is known about the molecular mechanisms underlying nerve-tumor interactions. An increasing number of studies have revealed that the genes associated with PNI are classical neurodevelopmental genes associated with neurodevelopmental processes. Therefore, the central hypothesis of this thesis was that nerve-tumor interactions result in part from an abnormal reactivation of the molecular pathways underlying the embryonic development of the nervous system. To test this hypothesis, public datasets from different types of cancer with high incidence of PNI were analyzed to identify molecular pathways common between these cancers. This analysis revealed that neurodevelopmental pathways accounted for 12 - 16% of the differentially expressed genes (DEGs), with axon guidance genes being markedly dysregulated. Overall, 17 different axon guidance gene families, including ephrin-Eph, semaphorin-neuropilin/plexin and slit-robo pathways were dysregulated. Further disruption of these pathways was a common feature across a number of cancers analyzed and their dysregulation had a significant impact on disease survival. Overall, this suggested that neurodevelopmental molecular pathways may contribute to tumor axonogenesis and PNI. 

These findings suggested a significant role of neurodevelopmental pathways in cancer dysregulation. Thus, a comprehensive understanding of the pathways during the nervous system development is imperative. Therefore, in my thesis, the embryo was used as a tool to study the mechanisms by which these molecular pathways influence axonogenesis more broadly. First, the role of the axon guidance genes Slit/Robo was examined during mouse neurodevelopment. Our results showed that Robo2 enrichment influences the migration and axonal projections of spinal ipsilateral neurons. In parallel, we investigated the role of alternative splicing of transcription factors as a mechanism of increase neuronal diversity. In particular we examined the expression dynamics of Lhx9, a transcription factor that controls the expression of the axon guidance gene Robo3. Lhx9 splice variants showed a differential expression at key developmental points in the spinal cord, suggesting Lhx9 splice dynamics plays an important role in neural guidance choices. 

In the third part of the thesis, I investigated the role of gap junctions, in nerve-tumor interactions, using pancreatic ductal adenocarcinoma (PDAC) cancer cells in vitro models. The connexin GJB2 emerged as the most overexpressed gap junction component in PDAC tumors. In vitro analysis, involving blocking gap junctions or connexin overexpression, revealed that gap junctions influenced PDAC cancer cell behaviors and properties. Further we developed a novel nerve-tumor assay and used it to examine the role of gap junction genes in PDAC cells neuronal growth. 

Overall, this thesis postulated that several key molecular pathways crucial for normal nervous system embryonic development, could underly nerve- tumor interactions during cancer development and progression.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2023. s. 81
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2272
Nyckelord
Perineural invasion, cancer, PDAC, axonogenesis, neurodevelopment, spinal cord, axon guidance, bioinformatics.
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi Neurovetenskaper Utvecklingsbiologi
Forskningsämne
biomedicinsk laboratorievetenskap
Identifikatorer
urn:nbn:se:umu:diva-216925 (URN)978-91-8070-221-8 (ISBN)978-91-8070-222-5 (ISBN)
Disputation
2023-12-13, NAT.D.360, Naturvetarhuset, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2023-11-22 Skapad: 2023-11-20 Senast uppdaterad: 2023-11-21Bibliografiskt granskad

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Wheaton, Benjamin JoelHäggström, Sara LeaMuppavarapu, MridulaGonzalez-Castrillon, Luz MariaWilson, Sara Ivy

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Wheaton, Benjamin JoelHäggström, Sara LeaMuppavarapu, MridulaGonzalez-Castrillon, Luz MariaWilson, Sara Ivy
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Developmental Dynamics
UtvecklingsbiologiMedicinsk genetikBiokemi och molekylärbiologi

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