Cell Intrinsic Modulation of Wnt Signaling Controls Neuroblast Migration in C. elegans

Mentink, Remco A.; Middelkoop, Teije C.; Rella, Lorenzo; Ji, Ni; Tang, Chung Yin; Betist, Marco C.; Oudenaarden, Alexander van; Korswagen, Hendrik C.

doi:10.1016/j.devcel.2014.08.008

Cited by 41 publications

(129 citation statements)

References 45 publications

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“…This hypothesis is consistent with previous observations that pyramidal precursors in the developing cortex express not only Wnt5A but also the non-canonical receptors Ror 1 and 2 (Endo et al, 2012). Intriguingly, a similar cell-intrinsic modulation of Wnt canonical as well as non-canonical signaling has been implicated in the control of neuroblast migration in C. elegans (Mentink et al, 2014), indicating that this regulatory mechanism, similarly to guidance by Wnt morphogenic gradient, is evolutionarily conserved. How Wnt5A expression is regulated remains to be determined.…”

Section: Discussionsupporting

confidence: 82%

“…Moreover, Wnt signaling has been implicated in dendritic development and synapse formation of cortical neurons in culture (Dickins and Salinas, 2013). Evidence indicates that Wnt proteins guide cell migration and that multiple Wnt ligands and receptors directly regulate cell polarity and motility in a variety of vertebrate and invertebrate systems (Lyuksyutova et al, 2003;Witze et al, 2008;Mentink et al, 2014). Whether there is a similar direct role of Wnt signaling in regulating neuronal migration in the mammalian cerebral cortex remains largely unexplored.…”

Section: Introductionmentioning

confidence: 98%

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Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

et al. 2015

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The precise timing of pyramidal cell migration from the ventricular germinal zone to the cortical plate is essential for establishing cortical layers, and migration errors can lead to neurodevelopmental disorders underlying psychiatric and neurological diseases. Here, we report that Wnt canonical as well as non-canonical signaling is active in pyramidal precursors during radial migration. We demonstrate using constitutive and conditional genetic strategies that transient downregulation of canonical Wnt/β-catenin signaling during the multipolar stage plays a critical role in polarizing and orienting cells for radial migration. In addition, we show that reduced canonical Wnt signaling is triggered cell autonomously by time-dependent expression of Wnt5A and activation of non-canonical signaling. We identify ephrin-B1 as a canonical Wnt-signaling-regulated target in control of the multipolar-to-bipolar switch. These findings highlight the critical role of Wnt signaling activity in neuronal positioning during cortical development.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 98%

Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

et al. 2015

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“…Loss of Wnt signaling inhibits neuroblast migration, neural differentiation, and suppression of the development of the forebrain. [35][36][37][38] Moreover, we previously reported that mutations in b-catenin contribute to ID in humans, 39,40 and mutations in d-catenin, some of which abrogate its biochemical interaction with b-catenin, can contribute to severe autism in females, 32 strengthening further the link between Wnt signaling and human neurodevelopmental disorders.…”

mentioning

confidence: 96%

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Blok

Madsen

Juusola³

et al. 2015

The American Journal of Human Genetics

219

280

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Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

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“…The Wnt/β-catenin pathway has been intensively studied in C. elegans, with a significant focus on Wnt-guided cell migration and the SYS-1/POP-1 Wnt asymmetry pathway, required for proper fate of seam cells and some neurons, while the role of BAR-1 in the Pn.p cells has remained less characterized (Eisenmann et al, 1998;Gleason et al, 2002;Harterink et al, 2011;Korswagen, 2002;Lin et al, 1998;Maloof et al, 1999;Mentink et al, 2014;Mila et al, 2015;Park and Priess, 2003;Shetty et al, 2005;Whangbo and Kenyon, 1999). While genetic evidence shows that β-catenin/BAR-1 is an inhibitor of the eff-1 gene, it is conventionally known to act as a transcriptional co-activator with the TCF/POP-1 protein, suggesting that the effect BAR-1 has on eff-1 is through another intermediate protein.…”

Section: Discussionmentioning

confidence: 99%

Variability in β-catenin pulse dynamics in a stochastic cell fate decision inC. elegans

Kroll

Tsiaxiras

Zon

2018

Preprint

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Stochastic cell fate decisions occur frequently during animal development. In many cases, individual cells randomly choose one cell fate out of a limited repertoire of fates, but with the relative frequency of the different possible fates tightly controlled. It is not understood how signaling networks enable such cell-autonomous stochastic decisions and what network properties control the relative frequency of the resulting cell fates. To address these questions, we studied the differentiation of the C. elegans P3.p cell as a model system for a cellautonomous stochastic cell fate decision. We use a novel time-lapse microscopy technique to measure the single-cell dynamics of BAR-1/β-catenin and LIN-39/Hox, two key regulators of the network, while monitoring both the timing and outcome of the decision. Surprisingly, the timing of the decision is highly regulated, even in mutants that drastically alter the frequency of the cell fates. Using experimental data and modeling approaches, we find that a combination of variability in LIN-39 levels and variability in the timing of BAR-1/β-catenin signaling are noise sources that bias the stochastic decision. Our results highlight that a novel aspect of Wnt signaling can provide sufficient variation in a signaling network to enable a cell-autonomous stochastic cell fate decision in a multicellular organism.

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Cell Intrinsic Modulation of Wnt Signaling Controls Neuroblast Migration in C. elegans

Cited by 41 publications

References 45 publications

Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Variability in β-catenin pulse dynamics in a stochastic cell fate decision inC. elegans

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