Activin has direct long-range signalling activity and can form a concentration gradient by diffusion

McDowell, N; Zorn, Aaron M.; Crease, Devanand J.; Gurdon, J. B.

doi:10.1016/s0960-9822(06)00294-6

Cited by 104 publications

(88 citation statements)

References 35 publications

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“…Our results are consistent with previous work showing that a morphogen gradient in early Xenopus embryos is achieved by diffusion through intercellular space (Gurdon et al, 1994;McDowell et al, 1997;Scholpp and Brand, 2004;Williams et al, 2004) and that morphogen spreading can extend through nonresponsive cells. In a recent work, we have shown that Xbra induction can be detected behind a transcytosis-deficient graft (Jullien and Gurdon, 2005).…”

Section: Gradient Formationsupporting

confidence: 93%

“…According to the first idea, the concentration of activin just outside the outer Xbra border would be similar to the background level in the most distant parts of the animal cap; if the second idea is correct, the activin concentration would be higher just outside the Xbra border than in a more distant region. To examine the activin concentration just outside the outer Xbra border, we performed the following functional tests, because the activin concentration is too low to measure directly (approximately 40 pMol, McDowell et al, 1997).…”

Section: Boundary Sharpening Is Not the Results Of A Change In Gradienmentioning

confidence: 99%

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Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

Kinoshita

Jullien

Gurdon

2006

Developmental Dynamics

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Morphogen gradients play an important role in pattern formation in embryo. However, the interpretation of position in a morphogen gradient is not well understood. Because it is hard to analyze morphogen gradients especially in opaque embryos such as those of Xenopus, it is necessary to fix and section the embryo, thereby eliminating the possibility of real-time observation, and making more difficult the interpretation of events that take place in three dimensions. We describe here a two-dimensional preparation of cells from a Xenopus blastula animal cap, in which an activin concentration gradient appears to be formed and interpreted at the same rate and in the same way as in normal embryos. We use two-dimensional preparations of this kind to contribute the following new information about gradient formation and interpretation in embryo. We determine the dynamics of formation of an activin activity gradient in real time. We demonstrate that this gradient is established by diffusion of activin through intercellular space and does not require internalization of receptor or ligand. We also show that the generation of a boundary of gene expression depends on the interpretation, rather than a change of composition, of the concentration gradient. Developmental Dynamics 235:3189 -3198, 2006.

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Section: Gradient Formationsupporting

confidence: 93%

Section: Boundary Sharpening Is Not the Results Of A Change In Gradienmentioning

confidence: 99%

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

Kinoshita

Jullien

Gurdon

2006

Developmental Dynamics

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“…Although passive diffusion can form an activin gradient (54), recent studies highlight the role of endocytosis in shaping morphogen gradients. Successive rounds of endocytosis and resecretion have been proposed as one model for morphogen movement through tissue (55).…”

Section: Resultsmentioning

confidence: 99%

Regulation of Endocytosis of Activin Type II Receptors by a Novel PDZ Protein through Ral/Ral-binding Protein 1-dependent Pathway

Matsuzaki¹,

Hanai²,

Kishi³

et al. 2002

Journal of Biological Chemistry

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Using yeast two-hybrid screening, we have identified a mouse Postsynaptic density 95/Discs large/Zona occludens-1 (PDZ) protein that interacts with activin type II receptors (ActRIIs). We named the protein activin receptor-interacting protein 2 (ARIP2). ARIP2 was found to have one PDZ domain in the NH 2 -terminal region and interact specifically with ActRIIs among the receptors for the transforming growth factor ␤ family by the PDZ domain. Interestingly, overexpression of ARIP2 enhances endocytosis of ActRIIs and reduces activin-induced transcription in Chinese hamster ovary K1 cells. In addition, immunofluorescence co-localization studies indicated the direct involvement of ARIP2 in the intracellular translocation of ActRIIs by PDZ domain-mediated interaction. Moreover, we have identified that the COOH-terminal region of ARIP2 interacts with Ralbinding protein 1 (RalBP1). RalBP1 is a potential effector protein of small GTP-binding protein Ral and regulates endocytosis of epidermal growth factor and insulin receptors. The studies using deletion mutants of RalBP1 and constitutively GTP and GDP binding forms of Ral indicate that ARIP2 regulates endocytosis of ActRIIs through the Ral/RalBP1-dependent pathway, and the GDP-GTP exchange of Ral is critical for this regulation.Activin, a member of the TGF-␤ 1 superfamily, has a broad range of physiological activities including hematopoiesis, bone morphogenesis, neurogenesis, and hormone action (1-5). These various actions on cell proliferation, differentiation, and apoptosis are dependent upon target cells. Activin transduces its signal via heteromeric complexes composed of two different serine/threonine kinase receptors, termed type I and type II (6 -8). Upon ligand binding, the type II receptor transphosphorylates and activates the type I receptor kinase at the membrane region. Then, the type I receptor cytoplasmic domain interacts with intracellular signaling molecules, Smads, which regulate transcription of selected genes in a cell-specific manner (9, 10).In the current model, the functions of the ActRIIs are limited to ligand binding, type I receptor recruitment, and transphosphorylation. However, it is speculated that there are specific roles of the ActRIIs in activin signaling. For example, the serine/threonine kinase domains of ActRIIs are constitutively activated, and ActRIIs exist as homooligomers (probably homodimers) even in the absence of ligands (11,12). These data suggest the existence of a strict monitoring mechanism for type II receptor kinase activity. Furthermore, multiple forms of ActRIIs exist; two subtypes of activin type II receptors, ActRIIA and ActRIIB, each of which is encoded by individual genes, are known (13,14). Several alternative splicing variants have also been found in each subtype (14 -16). For example, activin type IIA-N receptor, a splicing product of ActRIIA, is specifically expressed in neural cells and is thought to mediate neuronalspecific activin action. In a previous report, we noted the identification of a PDZ protein called a...

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“…A possible explanation is that the large number of additional activin binding sites generated from the transgene product in pyramidal cells trap activin molecules, thereby making them unavailable for activin receptors on interneurons. In view of the low level of activin in normal adult hippocampus 36 and the high diffusibility of activin, 37 this additional effect of the dominant-negative receptor approach might become relevant in our preparation. Alternatively, activin might act on pyramidal cells to control the expression and/or release of factors that modulate the activity of interneurons in a paracrine fashion.…”

Section: Discussionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Activin has direct long-range signalling activity and can form a concentration gradient by diffusion

Cited by 104 publications

References 35 publications

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

Regulation of Endocytosis of Activin Type II Receptors by a Novel PDZ Protein through Ral/Ral-binding Protein 1-dependent Pathway

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

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