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Compartmentalized morphogenesis in epithelia: from cell to tissue shape.

During development, embryonic tissues are shaped in a species-specific manner. Yet, across species, general classes of tissue remodeling events occur, such as tissue infolding and tissue elongation. The spatiotemporal control of these morphogenetic processes is responsible for the organization of different body plans, as well as for organogenesis. Cell morphogenesis in a mesenchyme contributes to the shaping of embryonic tissues. Epithelial cells, despite that they need to maintain an apicobasal organization, play an equally important role during morphogenesis. Moving from apical to basal, we review compartmentalized cellular rearrangements underlying tissue remodeling in Drosophila and compare them with those found in other organisms. Contractile activity at the apical surface triggers tissue folding and invagination. The regulation of adhesion at adherens junctions controls polarized neighbor exchange during intercalation and tissue elongation. Basolateral protrusive activity underlies other cases of intercalation. These localized cell shape changes are spatially regulated by developmental signals. Some signals define a local change in cell behavior (e.g., apical constriction), others orient a dynamic process in the plane of the tissue (e.g., junction remodeling).

Actins↗

Mechanics and function in heart morphogenesis.

For years, biomechanical engineers have studied the physical forces involved in morphogenesis of the heart. In a parallel stream of research, molecular and developmental biologists have sought to identify the molecular pathways responsible for embryonic heart development. Recently, several studies have shown that these two avenues of research should be integrated to explain how genes expressed in the heart regulate early heart function and affect physical morphogenetic steps, as well as to conversely show how early heart function affects the expression of genes required for morphogenesis. This review combines the perspectives of biomechanical engineering and developmental biology to lay out an integrated view of the role of mechanical forces in heart development.

Animals↗

Tissue interactions in the regulation of axon pathfinding during tooth morphogenesis.

Like many other organs, the tooth develops as a result of the epithelial-mesenchymal interactions. In addition, the tooth is a well-defined peripheral target organ for sensory trigeminal nerves, which are required for the function and protection of the teeth. Dental trigeminal axon growth and patterning are tightly linked with advancing tooth morphogenesis and cell differentiation. This review summarizes recent findings on the regulation of dental axon pathfinding, which have provided evidence that the development of tooth trigeminal innervation is controlled by epithelial-mesenchymal interactions. The early dental epithelium possesses the information to instruct tooth nerve supply, and signals mediating these interactions are part of the signaling networks regulating tooth morphogenesis. Tissue interactions, thus, appear to provide a central mechanism of spatiotemporally orchestrating tooth formation and dental axon navigation and patterning.

Animals↗

Recent advances in craniofacial morphogenesis.

Craniofacial malformations are involved in three fourths of all congenital birth defects in humans, affecting the development of head, face, or neck. Tremendous progress in the study of craniofacial development has been made that places this field at the forefront of biomedical research. A concerted effort among evolutionary and developmental biologists, human geneticists, and tissue engineers has revealed important information on the molecular mechanisms that are crucial for the patterning and formation of craniofacial structures. Here, we highlight recent advances in our understanding of evo-devo as it relates to craniofacial morphogenesis, fate determination of cranial neural crest cells, and specific signaling pathways in regulating tissue-tissue interactions during patterning of craniofacial apparatus and the morphogenesis of tooth, mandible, and palate. Together, these findings will be beneficial for the understanding, treatment, and prevention of human congenital malformations and establish the foundation for craniofacial tissue regeneration.

Animals↗

Role for retinoid signaling in left-right asymmetric digestive organ morphogenesis.

The looping events that establish left-right asymmetries in the vertebrate gut tube are poorly understood. Retinoic acid signaling is known to impact left-right development in multiple embryonic contexts, although its role in asymmetric digestive organ morphogenesis is unknown. Here, we show that the genes for retinaldehyde dehydrogenase (RALDH2) and a retinoic acid hydroxylase (CYP26A1) are expressed in complementary patterns in the Xenopus gut during looping. A late-stage chemical genetic assessment reveals that agonists and antagonists of retinoid signaling generate abnormal gut looping topologies, digestive organ heterotaxias, and intestinal malrotations. Accessory organ deformities commonly associated with intestinal malrotation in humans, such as annular pancreas, pancreas divisum, and extrahepatic biliary tree malformations, are also induced by distinct retinoid receptor agonists. Thus, late-stage retinoic acid signaling is likely to play a critical role in asymmetric gut tube morphogenesis and may underlie the etiology of several clinically relevant defects in the digestive system.

Aldehyde Dehydrogenase 1 Family↗

Retinoic acid is required for endodermal pouch morphogenesis and not for pharyngeal endoderm specification.

Because tissues from all three germ layers contribute to the pharyngeal arches, it is not surprising that all major signaling pathways are involved in their development. We focus on the role of retinoic acid (RA) signaling because it has been recognized for quite some time that alterations in this pathway lead to craniofacial malformations. Several studies exist that describe phenotypes observed upon RA perturbations in pharyngeal arch development; however, these studies did not address whether RA plays multiple roles at distinct time points during development. Here, we report the resulting phenotypes in the hindbrain, the neural crest-derived tissues, and the pharyngeal endoderm when RA synthesis is disrupted during zebrafish gastrulation and pharyngeal arch morphogenesis. Our results demonstrate that RA is required for the post-gastrulation morphogenesis and segmentation of endodermal pouches, and that loss of RA does not affect the length of the pharyngeal ectoderm or medial endoderm along the anterior-posterior axis. We also provide evidence that RA is not required for the specification of pharyngeal pouch endoderm and that the pharyngeal endoderm consists of at least two different cell populations, of which the pouch endoderm is sensitive to RA and the more medial pharyngeal endoderm is not. These results demonstrate that the developmental processes underlying pharyngeal arch defects differ depending on when RA signaling is disturbed during development.

Animals↗

Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis.

The mammary gland develops in a process known as branching morphogenesis, whereby a distal epithelial bud extends and bifurcates to form an extensive ductal network. Compared with other branched organs, such as the lung and kidney, little is known about the molecular basis of branching in the mammary gland. Here we report a microarray profiling strategy to identify novel genes that may regulate mammary branching. We microdissected terminal end bud (TEB) and mature duct microenvironments from beta-actin-green fluorescent protein reporter mice and compared their RNA expression profiles with epithelium-free mammary stroma by means of microarray. We identified 1,074 genes enriched in the TEB microenvironment, 222 genes enriched in the mature duct microenvironment, and 385 genes enriched in both TEB and mature duct microenvironments. The microarray correctly predicted the expression of genes known to be enriched in the epithelium (Ets-5) and stroma (MMP-14) of TEBs and in the mature duct microenvironment (MMP-3). The microarray also correctly predicted the localization of previously uncharacterized genes, such as the TEB-enriched SPRR-1a, the duct-enriched casein-gamma, and the general epithelial marker pleiotrophin. Analysis of genes enriched in TEBs revealed several genes in the Wnt (Wnt-2, Wnt-5a, Wnt-7b, Dsh-3, Frizzled-1, Frizzled-2), hedgehog (Dhh), ephrin (Ephrin-B1, Eph-A2), and transcription factor (Twist-1, Twist-2, Snail) families. In situ hybridization verified that these genes were enriched in the TEB epithelium (Wnt-5a, Wnt-7b, Dhh, Eph-A2) or TEB stroma (Wnt-2, Frizzled-1, Ephrin-B1). We discuss the potential roles of these genes in mammary branching morphogenesis.

Animals↗

HGF/SF-met signaling in the control of branching morphogenesis and invasion.

Hepatocyte growth factor/Scatter factor (HGF/SF) is a multifunctional growth factor which can induce diverse biological events. In vitro, these include scattering, invasion, proliferation and branching morphogenesis. In vivo, HGF/SF is responsible for many processes during embryonic development and a variety of activities in adults, and many of these normal activities have been implicated in its role in tumorgenesis and metastasis. The c-Met receptor tyrosine kinase is the only known receptor for HGF/SF and mediates all HGF/SF induced biological activities. Upon HGF/SF stimulation, the c-Met receptor is tyrosine-phosphorylated which is followed by the recruitment of a group of signaling molecules and/or adaptor proteins to its cytoplasmic domain and its multiple docking sites. This action leads to the activation of several different signaling cascades that form a complete network of intra and extracellular responses. Different combinations of signaling pathways and signaling molecules and/or differences in magnitude of responses contribute to these diverse series of HGF/SF-Met induced activities and most certainly are influenced by cell type as well as different cellular environments. In this review, we focus on HGF/SF-induced branching morphogenesis and invasion, and bring together recent new findings which provide insight into how HGF/SF, via c-Met induces this response.

Animals↗

Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro.

It has been proposed that proteases are important in endothelial cell behavior. We examined the contribution of the gelatinase/type IV collagenase system in an in vitro model of endothelial differentiation. Human umbilical vein endothelial cells rapidly align and form networks of tubes when cultured on a basement membrane preparation, Matrigel. Zymograms of culture supernates demonstrate a 72-kD and a 92-kD gelatinase activity; the cells produce most of the 72-kD gelatinase, whereas the 92-kD activity is derived entirely from the Matrigel. Addition of antibodies against type IV gelatinase/collagenase decreases the area of the tube network. Both tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, similarly decrease tube formation when added to cultures. Conversely, exogenous recombinant 72-kD gelatinase increases tube-forming activity. The effects of the anti-gelatinase antibodies and the TIMPs are not additive. Inhibition by either antibodies or TIMPs is greatest when they are added at culture initiation, suggesting that the protease activity is important in the early steps of morphogenesis. However, culture of the cells on Matrigel does not increase early expression of mRNA for the 72-kD gelatinase. Expression of message for the enzyme actually decreases during the course of the assay, while transcription of mRNAs for TIMPs increases, further supporting the concept that collagenases facilitate an early event in tube formation. These data demonstrate that gelatinase/type IV collagenase activity is important in endothelial cell morphogenesis on Matrigel, and suggest a role for collagenases in formation of new capillaries in vivo.

Amino Acid Sequence↗

Morphogenesis of the different types of photoreceptors of the chicken (Gallus domesticus) retina and the effect of amblyopia in neonatal chicken.

Despite the great variety in chicken photoreceptors, existing morphogenetic studies only deal with two types: rods and cones. We have therefore examined by scanning electron microscopy the first appearance and maturation of different retinal photoreceptors in 36 chicken embryos (Gallus domesticus), aged 5-19 days prehatching. On day 5 of incubation, chicken retinae were only composed of proliferating ventricular cells devoid of photoreceptors. On day 8, outer mitotic cells were separated from inner differentiating photoreceptors, by the transient layer of Chievitz. Ball-like protrusions appeared at the ventricular surface, representing the first signs of photoreceptor inner segment formation. From day 10 onward, double cones, single cones, and rods could be clearly distinguished, and occasional cilia were detected at their tip. On day 12, inner segments had increased in length and diameter, and frequently carried a cilium representing the beginning of outer segment formation. On day 14, most photoreceptors displayed a distinct outer segment. On day 19, photoreceptors had essentially assumed adult morphology. Based on the shape of their outer segments, two subtypes of cones and three subtypes of double cones could be distinguished. Throughout development, we observed microvilli close to maturing photoreceptors, either originating from their lateral sides, from their tip, or from Müller cells. Microvillus density peaked between day 12 and 14, indicating an important role in photoreceptor morphogenesis. Unilateral occlusion of the eyes of posthatching chicken reduced the proportion of double cones to single cones in the retina, indicating dependence of retinal morphogenesis upon functional activity of visual cells.

Amblyopia↗

The oral apparatus of Tetrahymena pyriformis, strain WH-6. II. Cytochalasin B inhibition of oral apparatus morphogenesis.

The effects of cytochalasin B on oral apparatus morphogenesis and cell division were studied in synchronized Tetrahymena pyriformis, strain WH-6 syngen 1. Cytochalasin B brought about the rapid arrest of oral apparatus primordium development when added prior to the completion of oral apparatus membranelle differentiation. Cells arrested in development did not divide. When cytochalasin B was added after this transition point, oral apparatus morphogenesis and cell division were completed. The effects of cytochalasin B could be reversed by washing it from the medium. Even though cytochalasin B (at 400 mug/ml) reduced protein synthesis by 30%, the data are consistent with the interpretation that cytochalasin B prevents an assembly process during the membranelle differentiation phase of oral apparatus development.

Animals↗

Epigenesis in developing avian scales. II. Cell proliferation in relation to morphogenesis and differentiation in the epidermis.

Throughout the early development of chicken scale epidermis, consisting of discrete placode and interplacode cell populations, morphogenesis and differentiation were examined from the standpoints of cell proliferation. From day 9.25 to day 11, active cell proliferation was observed only in the interplacode region, whereas the number of constituent cells increased considerably within the placode. After 26 hr of continuous labeling with [3H]thymidine (3H-TdR) in ovo, three regions could be recognized: (1) unlabeled placode on the distal edge, (2) labeled placode in both lateral and proximal sites to the unlabeled placode, and (3) extensively labeled interplacode on the most proximal site of the scale. Examination of the distribution pattern of labeled cells has demonstrated that a fraction of the cells in the interplacode transits and annexes only to the proximal side of the placode. Cells transit after mitosis, accompanied with changes in morphology and proliferation activity. During the period of cell transition, orientation of mitosis paralleled completely along the proximodistal axis of the scale. Cell marking with carbon particles was carried in organ cultures from day 10, and the changes in the position of marked cells were observed. The results confirm those obtained after continuous labeling with 3H-TdR. Various combinations of pulse-chase experiments with 3H-TdR clearly demonstrated the establishment of a cell lineage in which cells were aligned along the axis of the scale according to order of their birth. Along with a sudden resumption of active proliferation after day 11, a new class of cells (suprabasal cells) differentiated upward from the basal cells on the top region of the hump scale. At the first stage of development of suprabasal cells from day 11 to day 11.75, the direction of mitoses became preferentially polarized in the direction of axis vertical to the basal lamina. The important coordination of cell proliferation in relation to morphogenesis and cell differentiation is discussed.

Animals↗

Molecular biology of feather morphogenesis: a testable model for evo-devo research.

Darwin's theory describes the principles that are responsible for evolutionary change of organisms and their attributes. The actual mechanisms, however, need to be studied for each species and each organ separately. Here we have investigated the mechanisms underlying these principles in the avian feather. Feathers comprise one of the most complex and diverse epidermal organs as demonstrated by their shape, size, patterned arrangement and pigmentation. Variations can occur at several steps along each level of organization, leading to highly diverse forms and functions. Feathers develop gradually during ontogeny through a series of steps that may correspond to the evolutionary steps that were taken during the phylogeny from a reptilian ancestor to birds. These developmental steps include 1) the formation of feather tract fields on the skin surfaces; 2) periodic patterning of the individual feather primordia within the feather tract fields; 3) feather bud morphogenesis establishing anterio-posterior (along the cranio-caudal axis) and proximo-distal axes; 4) branching morphogenesis to create the rachis, barbs and barbules within a feather bud; and 5) gradual modulations of these basic morphological parameters within a single feather or across a feather tract. Thus, possibilities for variation in form and function of feathers occur at every developmental step. In this paper, principles guiding feather tract formation, distributions of individual feathers within the tracts and variations in feather forms are discussed at a cellular and molecular level.

Animals↗

Avian scale development. Absence of an "epidermal placode" in reticulate scale morphogenesis.

Timed-sequence studies have shown that reticulate scales on the ventral footpads of birds do not undergo "epidermal placode" formation during their morphogenesis, but arise as symmetrical evaluations similar to the scales of snakes and lizards. Unlike the scutellate scales on the dorsal surface of the foot, in which the formation of an "epidermal placode" and its subsequent morphogenesis result in disticnt outer and inner epidermal surfaces, the reticulate scales elaborate only one type of epidermal surface.

Age Factors↗

An electron microscopic study on the type I pneumocyte in the cat: pre-natal morphogenesis.

This investigation describes the pre-natal morphogenesis of the type I pneumocyte subsequent to its differentiation from pulmonary epithelium. Cells lining subpleural alveolar septa were photographed from serial sections with the electron microscope, and a three-dimensional representation of each cell was obtained by transferring the contours of the cell membranes from montages to transparent plastic sheets which were then spaced to scale and stacked. The results of this study indicate that: The nascent blood-air barrier of a 50-day reconstructed cell was twice as thick as the average definitive barrier; definitive barrier thickness was observed in some areas in a 63-day reconstructed cell; the amorphous component of elastic tissue which appears peripherally in septal connective tissue during pre-natal morphogenesis may be directly juxtaposed to the basal lamina of the alveolar epithelium; the orientation of the cell junction between a pneumocyte and its neighboring cells, as observed in sections of alveolar septa, changes as the contour of the pneumocyte changes from simple abutment to overlapping patterns.

Animals↗

The morphogenesis of the thigh of the mouse with special reference to tetrapod muscle homologies.

In order to provide an ontogenetic basis for the establishment of tetrapod muscle homologies and for the analysis of complex mammalian muscle states, a descriptive analysis of the morphogenesis of the thigh of Mus musculus has been made. The pattern and sequence of muscle cleavage and the migrations of individual muscle primordia are characterized from the eleventh day of gestation, when cleavage begins, through early neonatal stages. Observations on skeletal differentiation and lumbosacral plexus formation are also included. Thigh muscle morphogenesis is compared to that in the lizard, Lacerta, (Romer, '42) and the chick (Romer, '27) and homologies identified. An onogenetic basis for the definition of ancestral and derived muscle states is provided in muscles that are morphologically variable in mammals. These include the gluteus minimus, gracilis, adductor brevis and several hamstring muscles. Certain muscles that show variable innervation patterns in adult mammals, i.e., pectineus, quadratus and adductor magnus, typically develop from premuscle regions that separate muscle anlagen innervated by different nerves. Two muscle anlagen appear in the embryonic mouse thigh and then disappear late in prenatal or early postnatal development. Comparisons with other mammals, especially the marsupial, Marmosa, reveal that these muscles are phylogenetic vestiges that degenerate before maturity. A sartorius vestige is identifiable through the thirteenth day of gestation. A tenuissimus anlage is present until shortly after birth and is clearly innervated by a branch of the peroneal nerve.

Animals↗

Computer-based detection of neonatal changes to branching morphogenesis reveals different mechanisms of and predicts prostate enlargement in mice haplo-insufficient for bone morphogenetic protein 4.

Early changes to branching morphogenesis of the prostate are believed to lead to enlargement of the gland in adult life. However, it has not been possible to demonstrate directly that alterations to branching during the developmental period have a permanent effect on adult prostate size. In order to examine branching morphogenesis in a quantitative manner in neonatal mice, a combination of imaging and computational technology was used to detect and quantify branching using bone morphogenetic protein 4 haplo-insufficient mice that develop enlarged prostate glands in adulthood. Accurate estimates were made of six parameters of branching, including prostate ductal length and volume and number of main ducts, branches, branch points, and tips. The results show that the prostate is significantly larger on day 3, well before the emergence of the phenotype in older animals. The ventral prostate is enlarged because the number of main epithelial ducts is increased; enlargement of the anterior prostate in mutant animals occurs because there are more branches. These lobe-specific mechanisms underlying prostate enlargement indicate the complex nature of gland pathology in mice, rather than a simple increase in weight or volume. This method provides a powerful means to investigate the aetiology of prostate disease in animal models prior to emergence of a phenotype in later life.

Animals↗

The in vitro effect of triamcinolone acetonide on branching morphogenesis in the fetal rat lung.

We have studied the effect of triamcinolone acetonide (TAC) on airway morphogenesis of the Sprague-Dawley fetal rat in whole organ lung cultures from day 15 to day 21 of equivalent gestational age (6 days in culture). TAC produced an increased number of peripheral buds from day 18 onward and the airway and airspaces had larger lumens. Airway branching was increased compared to controls, and there was a higher proportion of airway epithelium and a lower proportion of mesenchyme. Cell height was significantly lower in TAC treated lungs except on day 17. This was due to accumulation of glycogen prior to the increased branching activity. In both controls and TAC-treated lungs, peripheral bud number and volume proportion of epithelium increased with time in culture, whereas volume proportion of mesenchyme, mean chord length of airways and airspaces, and epithelial cell height decreased. These changes were more pronounced in the TAC-treated group and were significant. However, TAC-treated lungs were morphologically irregular. We conclude that TAC has a direct effect on airway morphogenesis and it promotes growth of morphologically abnormal lungs. TAC also appears to enhance airway branching and morphologic changes interpreted as increased epithelial maturation.

Animals↗