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BMP - a key signaling molecule in specification and morphogenesis of sensory structures
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cranial placodes are transient thickenings of the vertebrate embryonic head ectoderm that will give rise to sensory (olfactory, lens, and otic) and non-sensory (hypophyseal) components of the peripheral nervous system (PNS). In most vertebrate embryos, these four sensory placodes undergo invagination. Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures, like an epithelial pit/cup. The process of invagination is crucial during development as it plays an important role for the formation of the lens, inner ear, nasal cavity, and adenohypophysis. Using the chick as the model system the following questions were addressed. What signals are involved in placode invagination? Is there any common regulatory molecular mechanism for all sensory placode invagination, or is it controlled by unique molecular codes for each individual placode? Are placode invagination and acquisition of placode-specific identities two independent developmental processes or coupled together? To address this we used in vivo assays like electroporation and whole embryo culture. Our in vivo results provide evidence that RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination are regulated by a common BMP (Bone morphogenetic protein) dependent molecular mechanism. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two independent developmental processes.

BMP signals have been shown to be essential for lens development and patterning of the retina. However, the spatial and temporal requirement of BMP activity during early events of lens development has remained elusive. Moreover, when and how retinal cells are specified, and whether the lens plays any role for the early development of the retina is not completely known. To address these questions, we have used gain- and loss-of-function analyses in chick explant and intact embryo assays. Here, we show that during lens development BMP activity is both required and sufficient to induce the lens specific marker, L-Maf. After the L-Maf upregulation the cells are no longer dependent on BMP signaling for the next step of fiber cell differentiation, which is characterized by up-regulation of δ-crystallin expression. Regarding the specification of retinal cells our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character. Furthermore, from optic vesicle stages, BMP signals emanating from the lens are essential for maintaining eye-field identity, inhibiting telencephalic character and inducing neural retina cells.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 64 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1812
Keyword [en]
BMP signaling, Placode morphogenesis, lens, retina, olfactory, otic
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-119696ISBN: 978-91-7601-468-4 (print)OAI: oai:DiVA.org:umu-119696DiVA: diva2:922873
Public defence
2016-05-20, Hörsal B Unod T 9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-04-29 Created: 2016-04-25 Last updated: 2016-04-28Bibliographically approved
List of papers
1. BMP-induced L-Maf regulates subsequent BMP-independent differentiation of primary lens fibre cells
Open this publication in new window or tab >>BMP-induced L-Maf regulates subsequent BMP-independent differentiation of primary lens fibre cells
2011 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 240, no 8, 1917-1928 p.Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic protein (BMP) signals are essential for lens development. However, the temporal requirement of BMP activity during early events of lens development has remained elusive. To investigate this question, we have used gain- and loss-of-function analyses in chick explant and intact embryo assays. Here, we show that BMP activity is both required and sufficient to induce L-Maf expression, whereas the onset of δ-crystallin and initial elongation of primary lens fibre cells are BMP-independent. Moreover, before lens placode formation and L-Maf onset, but not after, prospective lens placodal cells can switch to an olfactory placodal fate in response to decreased BMP activity. In addition, L-Maf is sufficient to up-regulate δ-crystallin independent of BMP signals. Taken together, these results show that before L-Maf induction BMP activity is required for lens specification, whereas after L-Maf up-regulation, the early differentiation of primary lens fibre cells occurs independent of BMP signals.

Keyword
lens, development, lens fibre cells, differentiation, BMP, L-Maf, δ-crystallin, chick
National Category
Developmental Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-51584 (URN)10.1002/dvdy.22692 (DOI)000292772400005 ()21761477 (PubMedID)
Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2017-12-08Bibliographically approved
2. Neural retina identity is specified by lens-derived BMP signals
Open this publication in new window or tab >>Neural retina identity is specified by lens-derived BMP signals
2015 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 142, no 10, 1850-1859 p.Article in journal (Refereed) Published
Abstract [en]

The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity.

Place, publisher, year, edition, pages
The Company of Biologists LTD, 2015
Keyword
BMP, chick, development, eye, lens, neural retina
National Category
Cell and Molecular Biology Developmental Biology
Identifiers
urn:nbn:se:umu:diva-105258 (URN)10.1242/dev.123653 (DOI)000355208600014 ()25968316 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2017-12-04Bibliographically approved
3. Apical constriction and epithelial invagination are regulated by BMP activity
Open this publication in new window or tab >>Apical constriction and epithelial invagination are regulated by BMP activity
2015 (English)In: Biology open, ISSN 2046-6390, Vol. 4, no 12, 1782-1791 p.Article in journal (Refereed) Published
Abstract [en]

Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures through bending of the tissue. It is accompanied by apical constriction, in which the apical cell surface is reduced in relation to the basal cell surface. Although much is known about the intra-cellular molecular machinery driving apical constriction and epithelial invagination, information of how extra-cellular signals affect these processes remains insufficient. In this study we have established several in vivo assays of placodal invagination to explore whether the external signal BMP regulates processes connected to epithelial invagination. By inhibiting BMP activity in prospective cranial placodes, we provide evidence that BMP signals are required for RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination. The failure of placode invagination after BMP inhibition appears to be a direct consequence of disrupted apical accumulation of RhoA and F-actin, rather than changes in cell death or proliferation. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two distinct and separable developmental processes. In summary, our results provide evidence that BMP signals promote epithelial invagination by acting upstream of the intracellular molecular machinery that drives apical constriction and cell elongation.

Keyword
BMP, F-actin, Invagination, RhoA, Apical constriction, Placodes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-114017 (URN)10.1242/bio.015263 (DOI)000366672900021 ()26621830 (PubMedID)
Available from: 2016-01-15 Created: 2016-01-11 Last updated: 2016-04-28Bibliographically approved

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