On the Role of PDZ Domain-Encoding Genes in Drosophila Border Cell Migration

Aranjuez, George F.; Kudlaty, Elizabeth; Longworth, Michelle S.; McDonald, Jocelyn A.

doi:10.1534/g3.112.004093

Cited by 24 publications

(30 citation statements)

References 88 publications

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“…In vivo gain and loss of function of ephrin‐B1 demonstrate that ephrin B1 plays a crucial role in migration of pyramidal neurons to the cerebral cortex (Wu et al, ; Dimidschstein et al, ). Furthermore, targeting a selected class of genes by RNAi reveals that PDZ domain‐encoding genes such as cnk are involved in border cell migration in Drosophila (Aranjuez et al, ). Incorrect neuronal migration can cause several brain malformations and cognitive dysfunction (Gleeson & Walsh, ).…”

Section: Discussionmentioning

confidence: 99%

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

Kazeminasab

Taskiran

Fattahi

et al. 2018

American J of Med Genetics Pt B

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The advent of high‐throughput sequencing technologies has led to an exponential increase in the identification of novel disease‐causing genes in highly heterogeneous diseases. A novel frameshift mutation in CNKSR1 gene was detected by Next‐Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen‐activated protein kinase (MAPK) cascades. CNKSR1 interacts with proteins which have already been shown to be associated with intellectual disability (ID) in the MAPK signaling pathway and promotes cell migration through RhoA‐mediated c‐Jun N‐terminal kinase (JNK) activation. Lack of CNKSR1 transcripts and protein was observed in lymphoblastoid cells derived from affected patients using qRT–PCR and western blot analysis, respectively. Furthermore, RNAi‐mediated knockdown of cnk, the CNKSR1 orthologue in Drosophila melanogaster brain, led to defects in eye and mushroom body (MB) structures. In conclusion, our findings support the possible role of CNKSR1 in brain development which can lead to cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

Kazeminasab

Taskiran

Fattahi

et al. 2018

American J of Med Genetics Pt B

View full text Add to dashboard Cite

show abstract

“…Recently, we performed an RNA interference (RNAi) screen targeting PDZ domain-containing genes to identify regulators of border cell collective migration 40 , which provided a starting point to identify candidate GBM migration genes. Proteins that contain the PDZ proteinprotein interaction domain facilitate the formation of multi-protein scaffolding complexes with conserved roles in signaling, cell polarization, and adhesion, making them excellent candidates to regulate the collective migration of normal and cancer cells.…”

Section: Identification Of Candidate Csc Invasion Genes Via Border Cementioning

confidence: 99%

“…Proteins that contain the PDZ proteinprotein interaction domain facilitate the formation of multi-protein scaffolding complexes with conserved roles in signaling, cell polarization, and adhesion, making them excellent candidates to regulate the collective migration of normal and cancer cells. The majority of Drosophila PDZ-(PSD95/Dlg/ZO1-) domain genes were screened for the ability to promote border cell migration 40 (Fig. 3a).…”

Section: Identification Of Candidate Csc Invasion Genes Via Border Cementioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

et al. 2020

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Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development. Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs.

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“…Recently, we performed an RNA interference (RNAi) screen targeting PDZ domain-containing genes to identify those that regulate border cell collective migration 42 , which provided a starting point to identify candidate GBM migration genes. Proteins that contain the PDZ protein-protein interaction domain facilitate the formation of multi-protein scaffolding complexes with conserved roles in signaling, cell polarization, and adhesion, making them excellent candidates to regulate the collective migration of normal and cancer cells 43,44 .…”

Section: Identification Of Candidate Csc Invasion Genes Via Border Cementioning

confidence: 99%

“…We and others recently showed that inhibition of the Drosophila Rap1a homolog (Rap1) disrupted migration to the oocyte due to defects in actin-rich protrusions and altered cell-cell adhesion 57,58 . Rap1a is also regulated by the screen multi-hit gene, PDZ-GEF 42 (ortholog of human RapGEF2/PDZ-GEF1 and RapGEF6/PDZ-GEF2; Supplementary Table 1).…”

Section: Rap1a Levels Are Elevated In Gbm Patients and Correlate Withmentioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Volovetz

Berezovsky

Alban

et al. 2019

Preprint

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Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development.Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. RAP1A

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On the Role of PDZ Domain-Encoding Genes in Drosophila Border Cell Migration

Cited by 24 publications

References 88 publications

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

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