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Control of early development of the lens and the retina
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). (Lena Gunhaga)
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nervous system is composed of two separate compartments, the central and the peripheral nervous system. The peripheral nervous system (PNS) composed mainly of sensory organs transmits sensory information to the central nervous system (CNS) comprising the brain and the spinal cord. The CNS then processes this information and modifies the behaviour of the organism appropriately. To understand the functioning of these systems one has to understand how the different cell types belonging to these systems are generated during the course of embryonic development. Using the chick eye with the lens, which arises from the region that gives rise to components of PNS, and the retina, belonging to the CNS, as an embryonic model tissue the following questions were addressed: how do the BMP and the FGF signalling pathways affect developmental processes within the lens and retina? When do retinal cells get specified and how do the lens and the retina interact with each other during early development? These questions were addressed by using a combination of in vitro and in vivo assays in chick embryos. We show in chick that lens cells are committed to a lens identity, concomitant with the up-regulation of the lens specific marker, L-Maf. Before the onset of L-maf, or in the absence of ongoing BMP activity, lens cells switch to an olfactory fate. However, after cells have up-regulated L-Maf, they are no longer dependent upon BMP signaling for the next step of lens primary fiber differentiation, which is characterized by the onset of δ-crystallin. We provide evidence that the FGF signalling pathway is critical for regulating proliferation within the developing lens, while FGF and BMP signals cooperate with each other to regulate cell cycle exit. In addition we have characterized the expression of Equarin restricted to the differentiating population within the lens, and we show that this gene is subject to regulation by both FGF and BMP signalling. In the absence of FGF and BMP signals, Equarin expression is down-regulated similar to down-regulation of the cell cycle exit marker p27kip1. Over activation of BMP, but not FGF signals is sufficient to up-regulate Equarin expression within the lens. Concerning retinal cells, we provide evidence that retinal cells are not specified until stage 13 in chick. Prior to stage 13, retinal cells are initially specified as telencephalic cells. Our results indicate that prospective retinal cells require either BMP signals or lens tissue, to maintain a retinal identity and to promote further development of retinal cells.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2013. , 46 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1596
Keyword [en]
Lens, retina, BMP, FGF, chick
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-80192ISBN: 978-91-7459-725-7 (print)OAI: oai:DiVA.org:umu-80192DiVA: diva2:647357
Public defence
2013-10-04, Hörsal B, Unod T 9, Norrlands Universitetssjukhus(NUS), Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-09-13 Created: 2013-09-11 Last updated: 2013-09-13Bibliographically 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. A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells
Open this publication in new window or tab >>A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells
2012 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 16, 3266-3274 p.Article in journal (Refereed) Published
Abstract [en]

In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-64061 (URN)10.1091/mbc.E12-01-0075 (DOI)000312219900022 ()
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved
3. Specification of neural retina character by lens derived BMP signaling
Open this publication in new window or tab >>Specification of neural retina character by lens derived BMP signaling
2013 (English)Manuscript (preprint) (Other academic)
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-80210 (URN)
Note

this manuscript is still work in progress and has not been sent to any jounrnal for peer review yet

Available from: 2013-09-11 Created: 2013-09-11 Last updated: 2013-09-13Bibliographically approved

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