Browsing by Subject "morphogenesis"

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  • Jia, S.; Zhou, J.; Wee, Y.; Mikkola, M. L.; Schneider, P.; D'Souza, R. N. (2017)
    To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9(-/-) mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9(-/-) embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.
  • Kuony, Alison; Michon, Frederic (2017)
    As an element of the lacrimal apparatus, the lacrimal gland (LG) produces the aqueous part of the tear film, which protects the eye surface. Therefore, a defective LG can lead to serious eyesight impairment. Up to now, little is known about LG morphogenesis and subsequent maturation. In this study, we delineated elements of the cellular and molecular events involved in LG formation by using three epithelial markers, namely aSMA, Krt14, and Krt19. While aSMA marked a restricted epithelial population of the terminal end buds (TEBs) in the forming LG, Krt14 was found in the whole embryonic LG epithelial basal cell layer. Interestingly. Krt19 specifically labeled the presumptive ductal domain and subsequently, the luminal cell layer. By combining these markers, the Fucci reporter mouse strain and genetic fate mapping of the Krt14+ population, we demonstrated that LG epithelium expansion is fuelled by a patterned cell proliferation, and to a lesser extent by epithelial reorganization and possible mesenchymal-to-epithelial transition. We pointed out that this epithelial reorganization, which is associated with apoptosis, regulated the lumen formation. Finally, we showed that the inhibition of Notch signaling prevented the ductal identity from setting, and led to a LG covered by ectopic TEBs. Taken together our results bring a deeper understanding on LG morphogenesis, epithelial domain identity, and organ expansion.
  • Maidell-Hjort, Laura (Helsingfors universitet, 2016)
    Osa kallon ja kasvojen luista kehittyy elimistön kannalta ainutlaatuisella tavalla intramembranoottisesti suoraan mesenkyymistä. Siten osteoblastien erilaistumista säätelevien geenien mutaatiot tulevat usein selkeästi esiin kallon ja kasvojen alueen kehityshäiriöinä. Gli2 on Hedgehog-signaalireitin transkriptioaktivaattori, jonka tiedetään vaikuttavan osteoblastien erilaistumiseen. Sen mutaatiot aiheuttavat pään alueella erityisesti keskiviivadefektejä kuten holoprosenkefaliaa ja siihen liittyvää fenotyyppiä. Kuitenkin Gli2:n merkityksestä kallon luiden kehittymiseen ja muodon määräytymiseen tiedetään varsin vähän. Tutkielma koostuu kirjallisuuskatsauksesta sekä pilottitutkimuksesta, jossa kuvataan Gli2-poistogeenisten hiirten alizarin red -värjättyjen kallojen ja kasvojen luiden morfologiaa, ja täten pyritään selvittämään Gli2:n merkitystä näiden luiden kehityksessä. Hiirillä havaitaan muun muassa luukudoksen kehityksen viivästymistä sekä etenkin kuonon ja otsan alueella synostoottisia luusaumoja sekä suulakihalkioita. Kallon ja kasvojen luuston kehityksen ymmärtäminen on välttämätöntä suulakihalkioiden ja kraniosynostoosien tutkimuksen ja hoitojen kehittämisen kannalta.
  • Kurtzeborn, Kristen; Cebrian, Cristina; Kuure, Satu (2018)
    Classically, trophic factors are considered as proteins which support neurons in their growth, survival, and differentiation. However, most neurotrophic factors also have important functions outside of the nervous system. Especially essential renal growth and differentiation regulators are glial cell line-derived neurotrophic factor (GDNF), bone morphogenetic proteins (BMPs), and fibroblast growth factors (FGFs). Here we discuss how trophic factor-induced signaling contributes to the control of ureteric bud (UB) branching morphogenesis and to maintenance and differentiation of nephrogenic mesenchyme in embryonic kidney. The review includes recent advances in trophic factor functions during the guidance of branching morphogenesis and self-renewal versus differentiation decisions, both of which dictate the control of kidney size and nephron number. Creative utilization of current information may help better recapitulate renal differentiation in vitro, but it is obvious that significantly more basic knowledge is needed for development of regeneration-based renal therapies.
  • Montanari, Martti P.; Tran, Ngan Vi; Shimmi, Osamu (2022)
    Bone morphogenetic proteins (BMPs), members of the transforming growth factor-ss (TGF-ss) family, have been shown to contribute to embryogenesis and organogenesis during animal development. Relevant studies provide support for the following concepts: (a) BMP signals are evolutionarily highly conserved as a genetic toolkit; (b) spatiotemporal distributions of BMP signals are precisely controlled at the post-translational level; and (c) the BMP signaling network has been co-opted to adapt to diversified animal development. These concepts originated from the historical findings of the Spemann-Mangold organizer and the subsequent studies about how this organizer functions at the molecular level. In this Commentary, we focus on two topics. First, we review how the BMP morphogen gradient is formed to sustain larval wing imaginal disc and early embryo growth and patterning in Drosophila. Second, we discuss how BMP signal is tightly controlled in a context-dependent manner, and how the signal and tissue dynamics are coupled to facilitate complex tissue structure formation. Finally, we argue how these concepts might be developed in the future for further understanding the significance of BMP signaling in animal development.
  • Tolonen, Mari (Helsingin yliopisto, 2019)
    Epithelial cells form a barrier between the tissue and the external environment. Epithelial morphogenesis refers to the shaping of epithelial layers and is a key step in the development of organisms. The actin cytoskeleton provides the cell its form and during epithelial morphogenesis, produces force to shape the cells. To achieve this, the actin cytoskeleton is organized into protrusive and contractile networks. In a living cell, these actin networks are dynamic, as the filaments are constantly undergoing assembly and disassembly. Actin-binding proteins regulate the turnover of actin filaments, but in epithelial morphogenesis, the regulatory role of most of these proteins is still relatively unknown. In all multicellular organisms, actin disassembly is controlled by ADF/cofilin. ADF/cofilin activity is furthermore enhanced by other actin-binding proteins, one of which is cyclase-associated protein (CAP). CAP promotes actin turnover by accelerating ADF/cofilin mediated actin disassembly and in recycling actin monomers to sites of actin polymerization. Unlike ADF/cofilin that regulates actin disassembly throughout the whole cell, CAP could be subject to more specific spatial regulation, as loss of CAP leads to F-actin accumulation on the apical side of epithelial cells. However, the role of CAP in morphogenetic cell rearrangements remains poorly known. In addition, the in vivo role of the biochemical functions of CAP has not been elucidated. The aim of this master’s thesis is to describe the role of CAP in regulating the actin cytoskeleton in the follicular epithelium of the fruit fly Drosophila melanogaster. For this purpose, chimeric mutant flies with homozygous CAP loss of function mutation were generated. Subsequently, the effect of the CAP loss of function was observed in follicle cell populations undergoing morphogenetic changes. In addition, CAP loss of function was rescued with different transgenes producing mutant CAP proteins to identify the protein domains of CAP with in vivo significance. In addition, a Drosophila CAP specific antibody was purified to be used in immunostaining. The ovaries were imaged using confocal microscopy. In this thesis, it is shown that CAP loss of function caused accumulation of filamentous actin in all observed follicular cell populations. Surprisingly, the actin turnover was rescued by all of the used CAP rescue transgenes, but the mutant transgenes exhibited phenotypes resembling the CAP loss of function in other epithelial tissues. Moreover, CAP loss of function caused defects in the follicle cell movement and cell spreading. The loss of function also caused expression changes in other actin-binding proteins. The findings of these thesis support the current knowledge of CAP importance for functional actin turnover in the follicle cells, even though the protein domain necessary for in vivo function could not be deciphered. Moreover, this project provides indication that CAP has an indispensable role in dynamic morphogenetic processes in the epithelium. Together with other actin-binding proteins, CAP could regulate epithelial actin turnover in spatially directed manner, providing force for epithelial cell adhesions or protrusions.