<i>brother of cdo</i> (<i>umleitung</i>) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish

Bergeron, Sadie A.; Tyurina, Oksana V.; Miller, Emily E.; Bagas, Andrea; Karlstrom, Rolf O.

doi:10.1242/dev.057950

Cited by 35 publications

(50 citation statements)

References 76 publications

(94 reference statements)

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“…This idea was also supported by the expansion of the expression domain of nkx2.2 , a ventral forebrain Hh target gene28, observed in cdon morphants as compared with control embryos (Supplementary Fig. 3k–o).…”

Section: Resultsmentioning

confidence: 57%

“…Indeed Cdon −/− ; Boc −/− ; Gas1 −/− compound mutant embryos show a phenotype similar to that caused by the loss of Sonic hedgehog (Shh) function: strong facial malformations and failure of partition of the cerebral hemispheres and eye primordia22. In zebrafish, analysis of the uml(boc) mutant supports the idea that Boc acts as a positive regulator of Hh signalling in the ventral neural tube but might have an opposite function in the lower jaw28.…”

mentioning

confidence: 85%

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Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle

et al. 2014

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Patterning of the vertebrate optic vesicle into proximal/optic stalk and distal/neural retina involves midline-derived Hedgehog (Hh) signalling, which promotes stalk specification. In the absence of Hh signalling, the stalks are not specified, causing cyclopia. Recent studies showed that the cell adhesion molecule Cdon forms a heteromeric complex with the Hh receptor Patched 1 (Ptc1). This receptor complex binds Hh and enhances signalling activation, indicating that Cdon positively regulates the pathway. Here we show that in the developing zebrafish and chick optic vesicle, in which cdon and ptc1 are expressed with a complementary pattern, Cdon acts as a negative Hh signalling regulator. Cdon predominantly localizes to the basolateral side of neuroepithelial cells, promotes the enlargement of the neuroepithelial basal end-foot and traps Hh protein, thereby limiting its dispersion. This Ptc-independent function protects the retinal primordium from Hh activity, defines the stalk/retina boundary and thus the correct proximo-distal patterning of the eye.

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Section: Resultsmentioning

confidence: 57%

mentioning

confidence: 85%

Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle

et al. 2014

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“…This phenotype, very reminiscent of that of disp1 and boc mutant zebrafish embryos (Bergeron et al, 2011;Nakano et al, 2004), highlights the role of Sulf1 in assigning the ventral-most neural identity, acting as an enhancer of Hh signaling. It is noteworthy that sulf1 depletion, although preventing correct temporal activation of nkx2.2a, does not permanently inhibit its expression, which eventually occurs but with a severe delay.…”

Section: Sulf1 Is Required Over Time For Neural Patterning Establishmmentioning

confidence: 75%

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

et al. 2014

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In the ventral spinal cord, generation of neuronal and glial cell subtypes is controlled by Sonic hedgehog (Shh). This morphogen contributes to cell diversity by regulating spatial and temporal sequences of gene expression during development. Here, we report that establishing Shh source cells is not sufficient to induce the highthreshold response required to specify sequential generation of ventral interneurons and oligodendroglial cells at the right time and place in zebrafish. Instead, we show that Shh-producing cells must repeatedly upregulate the secreted enzyme Sulfatase1 (Sulf1) at two critical time points of development to reach their full inductive capacity. We provide evidence that Sulf1 triggers Shh signaling activity to establish and, later on, modify the spatial arrangement of gene expression in ventral neural progenitors. We further present arguments in favor of Sulf1 controlling Shh temporal activity by stimulating production of active forms of Shh from its source. Our work, by pointing out the key role of Sulf1 in regulating Shhdependent neural cell diversity, highlights a novel level of regulation, which involves temporal evolution of Shh source properties.

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“…; Bergeron et al . ). Given that these signaling pathways all have particular roles in OLG development, more work is required to determine if Cdon regulates OLG differentiation by one or more of these mechanisms.…”

Section: Discussionmentioning

confidence: 98%

A novel function of TBK1 as a target of Cdon in oligodendrocyte differentiation and myelination

Wang

Kennedy

Almazán

2016

Journal of Neurochemistry

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During central nervous system development, oligodendrocyte progenitors elaborate multiple branched processes to contact axons and initiate myelination. Using cultured primary rat oligodendrocytes (OLGs), we have recently demonstrated that a cell surface protein belonging to the immunoglobulin superfamily, cell adhesion molecule-related, down-regulated by oncogenes (Cdon), is important in initiating OLG differentiation and axon myelination by promoting the formation of branched cellular processes; however, the molecular mechanism by which Cdon regulates OLG differentiation is not known. Here, using Cdon immunoprecipitation (IP) and liquid chromatography-tandem mass spectrometry analysis, we identified serine/threonine kinase TANK-binding kinase 1 (TBK1) as a candidate novel target of Cdon. We confirmed this interaction using co-IP and immunofluorescence with TBK1 antibodies, showing that TBK1 partly co-localizes with Cdon along cellular processes in puncta-like structures. We show that TBK1 is expressed throughout OLG differentiation, and surprisingly, that levels of phosphorylated TBK1 (ser172) increase during OLG maturation, while total levels of TBK1 protein decrease. To investigate function, TBK1 expression was knocked down using siRNA in OLG primary cultures, reducing protein levels by 69%. Two myelin-specific proteins, myelin basic protein and myelin-associated glycoprotein, were similarly reduced when examined at day 2 and day 4 of OLG differentiation. Reduced Cdon or TBK1 expression also decreased Akt phosphorylation at Threonine 308 in OLG. Our findings provide evidence that a Cdon-TBK1 complex is associated with Akt phosphorylation and early OLG differentiation.

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brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish

Cited by 35 publications

References 76 publications

Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle

Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

A novel function of TBK1 as a target of Cdon in oligodendrocyte differentiation and myelination

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