Unsegmented Mesoderm Research Articles

Unique Features of River Lamprey (Lampetra fluviatilis) Myogenesis.

The river lamprey (L. fluviatilis) is a representative of the ancestral jawless vertebrate group. We performed a histological analysis of trunk muscle fiber differentiation during embryonal, larval, and adult musculature development in this previously unstudied species. Investigation using light, transmission electron (TEM), and confocal microscopy revealed that embryonal and larval musculature differs from adult muscle mass. Here, we present the morphological analysis of L. fluviatilis myogenesis, from unsegmented mesoderm through somite formation, and their differentiation into multinucleated muscle lamellae. Our analysis also revealed the presence of myogenic factors LfPax3/7 and Myf5 in the dermomyotome. In the next stages of development, two types of muscle lamellae can be distinguished: central surrounded by parietal. This pattern is maintained until adulthood, when parietal muscle fibers surround the central muscles on both sides. The two types show different morphological characteristics. Although lampreys are phylogenetically distant from jawed vertebrates, somite morphology, especially dermomyotome function, shows similarity. Here we demonstrate that somitogenesis is a conservative process among all vertebrates. We conclude that river lamprey myogenesis shares features with both ancestral and higher vertebrates.

Genetic regulation of amphioxus somitogenesis informs the evolution of the vertebrate head mesoderm.

The evolution of vertebrates from an ancestral chordate was accompanied by the acquisition of a predatory lifestyle closely associated to the origin of a novel anterior structure, the highly specialized head. While the vertebrate head mesoderm is unsegmented, the paraxial mesoderm of the earliest divergent chordate clade, the cephalochordates (amphioxus), is fully segmented in somites. We have previously shown that fibroblast growth factor signalling controls the formation of the most anterior somites in amphioxus; therefore, unravelling the fibroblast growth factor signalling downstream effectors is of crucial importance to shed light on the evolutionary origin of vertebrate head muscles. By using a comparative RNA sequencing approach and genetic functional analyses, we show that several transcription factors, such as Six1/2, Pax3/7 and Zic, act in combination to ensure the formation of three different somite populations. Interestingly, these proteins are orthologous to key regulators of trunk, and not head, muscle formation in vertebrates. Contrary to prevailing thinking, our results suggest that the vertebrate head mesoderm is of visceral and not paraxial origin and support a multistep evolutionary scenario for the appearance of the unsegmented mesoderm of the vertebrates new 'head'.

4D imaging reveals stage dependent random and directed cell motion during somite morphogenesis

Somites are paired embryonic segments that form in a regular sequence from unsegmented mesoderm during vertebrate development. Although transient structures they are of fundamental importance as they generate cell lineages of the musculoskeletal system in the trunk such as cartilage, tendon, bone, endothelial cells and skeletal muscle. Surprisingly, very little is known about cellular dynamics underlying the morphological transitions during somite differentiation. Here, we address this by examining cellular rearrangements and morphogenesis in differentiating somites using live multi-photon imaging of transgenic chick embryos, where all cells express a membrane-bound GFP. We specifically focussed on the dynamic cellular changes in two principle regions within the somite, the medial and lateral domains, to investigate extensive morphological transformations. Furthermore, by using quantitative analysis and cell tracking, we capture for the first time a directed movement of dermomyotomal progenitor cells towards the rostro-medial domain of the dermomyotome, where skeletal muscle formation initiates.

Embryonic Origin and Patterning of Cranial Muscle in the Mexican Axolotl ( Ambystoma mexicanum )

Cranial muscles play critical roles in numerous and diverse functions, including feeding, respiration, facial expression and (in some groups) vocalization. Despite the conservation of their basic structure in vertebrate evolution, cranial muscles have also played a significant role in evolutionary transitions among species. Here, we employ embryonic transplantations, using GFP-transgenic axolotls as donors, to determine the mesodermal contribution to cranial bone, cartilage and muscle. Expression patterns of cranial mesoderm markers are also analyzed within developing muscles. We define the axial level where unsegmented mesoderm can contribute to head muscles in the axolotl. Analysis of the posterior limit of unsegmented myogenic mesoderm indicates close overlap with the head-trunk boundary in the somites. This may help explain some of the differences in fate maps for muscles of birds and amphibians in the posterior head. Finally, gene expression analysis reveals markers for muscle groups important to the evolution of early tetrapods, including the gill levators.

An analysis of segmentation dynamics throughout embryogenesis in the centipede Strigamia maritima

BackgroundMost segmented animals add segments sequentially as the animal grows. In vertebrates, segment patterning depends on oscillations of gene expression coordinated as travelling waves in the posterior, unsegmented mesoderm. Recently, waves of segmentation gene expression have been clearly documented in insects. However, it remains unclear whether cyclic gene activity is widespread across arthropods, and possibly ancestral among segmented animals. Previous studies have suggested that a segmentation oscillator may exist in Strigamia, an arthropod only distantly related to insects, but further evidence is needed to document this.ResultsUsing the genes even skipped and Delta as representative of genes involved in segment patterning in insects and in vertebrates, respectively, we have carried out a detailed analysis of the spatio-temporal dynamics of gene expression throughout the process of segment patterning in Strigamia. We show that a segmentation clock is involved in segment formation: most segments are generated by cycles of dynamic gene activity that generate a pattern of double segment periodicity, which is only later resolved to the definitive single segment pattern. However, not all segments are generated by this process. The most posterior segments are added individually from a localized sub-terminal area of the embryo, without prior pair-rule patterning.ConclusionsOur data suggest that dynamic patterning of gene expression may be widespread among the arthropods, but that a single network of segmentation genes can generate either oscillatory behavior at pair-rule periodicity or direct single segment patterning, at different stages of embryogenesis.

Spatio‐temporal expression of MRF4 transcripts and protein during Xenopus laevis embryogenesis

Whereas there have been extensive studies of the expression of XMyf5 and XMyoD during Xenopus embryogenesis, nothing is known about the spatio-temporal accumulation of XMRF4 transcripts and protein. In this report, we describe the cloning and characterization of two full-length MRF4 cDNAs and of their proximal promoters in Xenopus laevis. The comparison of the relative transcript levels of the XMRF4-a and -b genes in developing and adult muscles is highly suggestive of specific functions for the corresponding XMRF4 proteins. Whole-mount embryo in situ hybridization revealed the first XMRF4 transcripts in the more differentiated anterior myocytes of the embryo when the myosin heavy chain E3 mRNA begins to be detectable. XMRF4 mRNA accumulation later extended posteriorly but was never detected in the posterior unsegmented mesoderm, in contrast to XMyoD and XMyf-5. Whole-mount embryo immunohistochemistry revealed that XMRF4 protein accumulated in somite nuclei slightly after XMRF4 transcripts.

Temperature and the expression of myogenic regulatory factors (MRFs) and myosin heavy chain isoforms during embryogenesis in the common carpCyprinus carpioL.

Embryos of the common carp, Cyprinus carpio L., were reared from fertilization of the eggs to inflation of the swim bladder in the larval stage at 18 and 25 degrees C. cRNA probes were used to detect transcripts of the myogenic regulatory factors MyoD, Myf-5 and myogenin, and five myosin heavy chain (MyHC) isoforms during development. The genes encoding Myf-5 and MyoD were switched on first in the unsegmented mesoderm, followed by myogenin as the somites developed. Myf-5 and MyoD transcripts were initially limited to the adaxial cells, but Myf-5 expression spread laterally into the presomitic mesoderm before somite formation. Two distinct bands of staining could be seen corresponding to the cellular fields of the forming somites, but as each furrow delineated, Myf-5 mRNA levels declined. Upon somite formation, MyoD expression spread laterally to encompass the full somite width. Expression of the myogenin gene was also switched on during somite formation, and expression of both transcripts persisted until the somites became chevron-shaped. Expression of MyoD was then downregulated shortly before myogenin. The expression patterns of the carp myogenic regulatory factor (MRF) genes most-closely resembled that seen in the zebrafish rather than the rainbow trout (where expression of MyoD remains restricted to the adaxial domain of the somite for a prolonged period) or the herring (where expression of MyoD persists longer than that of myogenin). Expression of two embryonic forms of MyHC began simultaneously at the 25-30 somite stage and continued until approximately two weeks post-hatch. However, the three adult isoforms of fast muscle MyHC were not detected in any stage examined, emphasizing a developmental gap that must be filled by other, as yet uncharacterised, MyHC isoform(s). No differences in the timing of expression of any mRNA transcripts were seen between temperature groups. A phylogenetic analysis of the MRFs was conducted using all available full-length amino acid sequences. A neighbour-joining tree indicated that all four members evolved from a common ancestral gene, which first duplicated into two lineages, each of which underwent a further duplication to produce Myf-5 and MyoD, and myogenin and MRF4. Parologous copies of MyoD from trout and Xenopus clustered closely together within clades, indicating recent duplications. By contrast, MyoD paralogues from gilthead seabream were more divergent, indicating a more-ancient duplication.

Spatial and temporal pattern of Fgf-8 expression during chicken development.

This study analyzes the temporal and spatial expression pattern of Fgf-8 over a continuous series of developmental stages. Special emphasis is laid on the paraxial mesoderm where Fgf-8 expression is highly dynamic. Whereas the anterior portion of the unsegmented mesoderm is devoid of expression, Fgf-8 is upregulated in the posterior half of a newly formed somite. Soon after somite formation, this highly localized expression gives way to a more diffuse pattern of Fgf-8 expression at low levels in presumptive sclerotomal cells. During later somite maturation, transcripts become restricted to the myotome. Co-staining with the myotome marker MyoD reveals that Fgf-8 expression defines a subpopulation of muscle precursor cells.

Inhibition of noggin expression in the dorsal neural tube by somitogenesis: a mechanism for coordinating the timing of neural crest emigration

We have previously shown that axial-dependent delamination of specified neural crest cells is triggered by BMP4 and negatively regulated by noggin. Increasing activity of BMP4 towards the rostral part of the axis is achieved by graded expression of noggin in the dorsal neural tube, the latter being high opposite unsegmented mesoderm, and progressively downregulated facing epithelial and dissociating somites, coinciding in time and axial level with initial delamination of neural crest cells (Sela-Donenfeld, D. and Kalcheim, C. (1999) Development 126, 4749-4762). Here we report that this gradient-like expression of noggin in the neuroepithelium is controlled by the paraxial mesoderm. Deletion of epithelial somites prevented normal downregulation of noggin in the neural tube. Furthermore, partial ablation of either the dorsal half or only the dorsomedial portion of epithelial somites was sufficient to maintain high noggin expression. In contrast, deletion of the segmental plate had no effect. These data suggest that the dorsomedial region of developing somites produces an inhibitor of noggin transcription in the dorsal neural tube. Consistent with this notion, grafting dissociating somites in the place of the unsegmented mesoderm precociously downregulated the expression of noggin and triggered premature emigration of neural crest progenitors from the caudal neural tube. Thus, opposite the unsegmented mesoderm, where noggin expression is high in the neural tube, BMP4 is inactive and neural crest cells fail to delaminate. Upon somitogenesis and further dissociation, the dorsomedial portion of the somite inhibits noggin transcription. Progressive loss of noggin activity releases BMP4 from inhibition, resulting in crest cell emigration. We propose that this inhibitory crosstalk between paraxial mesoderm and neural primordium controls the timing of neural crest delamination to match the development of a suitable mesodermal substrate for subsequent crest migration.

Spatial Expression of Two Tadpole Stage Specific Myosin Heavy Chains in <i>Xenopus laevis</i>

Vertebrate skeletal muscles contain a family of myosin heavy chain (MyHC) proteins whose expression varies with clonal origin, developmental age, hormonal state, and innervation patterns. The number of MyHC genes and their regulation have been intensely studied in mammals and birds. However, Comparatively little is known about MyHC expression in other vertebrates. To understand better MyHC regulation in amphibians, I have examined the fiber type expression of two tadpole stage-specific MyHC transcripts in Xenopus laevis. cDNAs for these transcripts, called MyHC E3 and MyHC E19, were used to synthesize digoxigenin labeled antisense RNA probes. In situ hybridization of these probes revealed that MyHC E3 was expressed through the myotome but was most abundant in the core fibers of the axial muscles, which are larval type II. In contrast, E19 was expressed most abundantly in the small diameter peripheral fibers of the axial muscles, which are larval type I. Transcripts of both genes were detected exclusively in skeletal muscles neither heavy chain was expressed in cardiac muscle, smooth muscle, or lymph heart muscle. E3 expression was first detected at late gastrula in both segmented and unsegmented dorsal mesoderm. It remained abundant throughout premetamorphosis in myotomal muscle, and was also found in the levator hyoideus and mandibularis muscle of the head, and in abdominal wall muscles. In contrast, E19 was first detected at tailbud in the tail tip and its expression spread anteriorly among larval type I and type II fibers of the myotome and head muscles during the next few hours of development. The patterns of expression suggest that MyHC E3 is expressed predominately in larval type II fibers, and MyHC E19 is initially expressed predominately in larval type I fibers but as development proceeds is expressed in both type I and type II.

Trunk neural crest origin of caudal fin mesenchyme in the zebrafishBrachydanio rerio

The origin of fin mesenchyme and the cells forming the distal fin ray skeleton in fishes is unknown, but is often assumed to be the neural crest. To test this possibility, a series of experiments have been done using a vital cell marking technique to label candidate progenitor cell populations in early zebrafish embryos. Injections of the fluorescent membrane probe DiI were made in discrete focal points into the dorsal aspect of the caudal neural keel before trunk neural crest cell emigration at that axial level in embryos at the 15-20 somite stage. As controls, injections were made into both paraxial, unsegmented mesoderm, and somitic mesoderm before somite elevation, ventral and lateral to the dorsal keel injection site. Only after injection into the neural keel site were labelled cells subsequently found in the fin mesenchyme (along with labelling of other cells types traditionally regarded as crest derived). These data provide the first experimental evidence that early fin bud mesenchyme contains a contribution from the trunk neural crest, and support the hypothesis that the dermal skeleton depends upon a crest-derived mesenchyme for its formation. We suggest that a causal link between neural crest-derived mesenchyme and the development of the exoskeleton has been evolutionary conserved throughout the neural crest of teleosts but has been lost in the trunk crest of higher vertebrates.

Expression of the neural cell adhesion molecule and polysialic acid during early mouse embryogenesis.

The expression of the neural cell adhesion molecule (N-CAM) and alpha 2-8 linked polysialic acid (PSA), which is believed to be predominantly expressed on N-CAM, was investigated during early embryonic development of the mouse (embryonic days 7.5 to 10.0). By immunocytochemistry, in tissue sections, N-CAM and PSA were not detectable at embryonic day 7.5 but were expressed in the prominent body regions such as somites, unsegmented mesoderm, developing heart, and neuroectoderm at embryonic day 8.0 N-CAM and PSA immunoreactivities were always predominantly associated with the plasma membrane. No tissue could be detected which was positive for PSA but negative for N-CAM. In Western blot analysis of whole embryos, by contrast, only the lightly sialylated and PSA-negative 180 and 140 kD isoforms of N-CAM were present at embryonic day 8.0 and strong expression of PSA-bearing, heavily sialylated N-CAM was not detectable before embryonic day 10.0. In Western blot analysis of N-CAM immunoaffinity purified from whole embryos and digested with neuraminidase as well as in Northern blot analysis, the 120 kD isoform of N-CAM or its corresponding mRNA were not expressed in detectable amounts during the time period investigated.

Characterization of the extracellular matrix during somitogenesis in the long-tailed monkey (Macaca fascicularis).

The composition of the extracellular matrix (ECM) associated with somitogenesis (stages 10-14) in the long-tailed monkey (Macaca fascicularis) was examined using peroxidase immunocytochemistry. A distinct temporal and spatial staining pattern was demonstrated for each component examined. Fibronectin (FN), laminin (LM) and hyaluronic acid (HA) were associated with the somite at each developmental stage, while no chondroitin sulfate (CS) staining was evident until stages 13/14. The basement membrane and matrix fibers linking the somites to the surrounding epithelia stained for FN, LM and HA. Localization of LM and HA between somite cells was observed at each stage, whereas FN and CS reactivity within the somitic tissue was only observed between sclerotome cells at stages 13/14. Whereas FN- and HA-positive fibers surrounded the unsegmented mesoderm, HA, and to a lesser extent LM, were located within the presomitic tissue. Comparisons are made with earlier studies conducted in rodent and avian embryos which indicate that these ECM components may play a regulatory role in primate somitogenesis.

An evaluation of myelomeres and segmentation of the chick embryo spinal cord

We have investigated whether the neuromeres of the developing chick spinal cord (myelomeres) are manifestations of intrinsic segmentation of the CNS by studying the patterns of cell proliferation and neuronal differentiation. Treatment of 2-day embryos with colchicine does produce exaggerated myelomeres, in confirmation of Källén (Z. Anat. Entwickl.-Gesch. 123, 309-319, 1962). However, this does not imply that myelomeres are segmental proliferation centres: the undulations caused by colchicine are irregular alongside the unsegmented mesoderm, and another mitotic inhibitor, bromodeoxyuridine, has no such effects. In contrast to lower vertebrate embryos, there is no evidence for segmental groups of primary motor neurons in the chick: the earliest motor neurons express cholinesterase, and project their axons into the adjacent sclerotome, at random positions in relation to the somite boundaries. The population of motor neurons projecting HRP-labelled axons into a single somite lies out of phase with both myelomere and somite, and is placed symmetrically about the anterior half-sclerotome. The earliest intrinsic spinal cord neurons, as stained with zinc iodide-osmium tetroxide or anti-68 x Mr neurofilament antibody, show no segmental patterns of differentiation. We conclude that, in contrast to the rhombomeres of the developing hindbrain, myelomeres are not matched by segmental groupings of differentiating nerve cells, and result from mechanical moulding of the neuroepithelium by the neighbouring somites.

Regional variations in the tightness of the ectodermal epithelium in the developing chick embryo: A study using ion‐sensitive microelectrodes

In 2-day-old avian embryos there is a rosto-caudal gradient of interstitial pH (Gillespie and McHanwell: Cell Tissue Res., 247:445-451, '87). Neither the developmental significance nor the basic cellular mechanisms underlying this phenomenon has been studied. The present paper provides information about the interstitial potassium and calcium ion concentrations and the movement of these ions across the ectodermal epithelium. The data suggests a possible explanation for the longitudinal pH gradient in the embryo. The concentrations of potassium and calcium ions in the interstitial spaces were measured with ion-sensitive and conventional microelectrodes. In embryos bathed in solution containing 1 mM potassium, the potassium concentration in the region of the mesencephalon was 5.1 +/- 0.7 mM while in the region of the unsegmented mesoderm it was significantly lower at 3.3 +/- 0.4 mM (mean +/- S.E., n = 16). If embryos are exposed to extra-embryonic solutions containing 30 mM potassium, the K+ concentration in the mesencephalon is 13.0 +/- 0.8 mM and higher at 15.4 +/- 1.2 mM in the unsegmented mesoderm (n = 12). In embryos bathed in solutions containing 0.1 mM calcium, the interstitial calcium was found to be 1.1 +/- 0.52 mM in the mesencephalon and 0.42 +/- 0.19 mM in the unsegmented mesoderm (n = 3). In comparison, embryos bathed in solution containing 10 mM calcium had 1.9 +/- 0.2 mM rostrally compared to 3.71 +/- 0.63 mM caudally (n = 10). Thus it is possible to generate intra-embryonic ion gradients dependent upon the extra-embryonic ion concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The somitic level of origin of embryonic chick hindlimb muscles

Studies of avian chimeras made by transplanting groups of quail somites into chick embryos have consistently shown that the muscle cells of the hindlimb are derived from the adjacent somites, however, the pattern of cell distribution from individual somites to individual hindlimb muscles has not been characterized. I have mapped quail cell distribution in the chick hindlimb after single somite transplantation to determine if cells from an individual somite populate discrete limb muscle regions and if there is a spatial correspondence between a muscle's somitic level of origin and the known spinal cord position of its motoneuron pool. At stages 15–18 single chick somites or equivalent lengths of unsegmented somitic mesoderm adjacent to the prospective hindlimb region were replaced with the corresponding tissue from quail embryos. At stages 28–34, quail cell distribution was mapped within individual thigh muscles and shank muscle regions. A quail-specific antiserum and Feulgen staining were used to identify quail cells. Transplants from somite levels 26–33 each gave rise to consistent quail cell labeling in a unique subset of limb muscles. The anteroposterior positions of these subsets corresponded to that of the transplanted somitic tissue. For example, more anterior or anteromedial thigh muscles contained quail cells when more anterior somitic tissue had been transplanted. For the majority of thigh muscles studied and for shank muscle groups, there was also a clear correlation between somitic level of origin and motoneuron pool position. These data are compatible with the hypothesis that motoneurons and the muscle cells of their targets share axial position labels. The question of whether motoneurons from a specific spinal cord segment recognize and consequently innervate muscle cells derived from the same axial level during early axon outgrowth is addressed in the accompanying paper (C. Lance-Jones, 1988, Dev. Biol. 126, 408–419) . Quail cell distribution was also mapped in chick embryos in which quail somites or unsegmented mesoderm had been placed 2–3 somites away from their position of origin. In all cases donor somitic tissues contributed to muscles in accord with their host position. These results indicate that muscle cell precursors within the somites are not specified to migrate to a predetermined target region.

Somitogenesis in the mouse embryo

This report describes the initiation of somitogenesis in the mouse embryo. Correlations are made with fibronectin distribution around the unsegmented mesoderm and the distribution of cytoskeletal elements within the cells as they undergo morphogenetic movements. The same temporal and topological changes in fibronectin, laminin, and cytoskeletal elements are seen in mouse somitogenesis as in the chick embryo. A notable exception is that the epithelial stage of somitogenesis in the mouse does not form a closed vesicle as it does in the chick. In the mouse the mesial portion of the forming somite does not become epithelial before the migration of sclerotomal cells.

Myoblasts and myoblast-conditioned medium attract the earliest spinal neurites from frog embryos.

A study was made of the capacity of newly segmented somites, unsegmented mesoderm and medium conditioned by each of these tissues to attract the growth of the earliest spinal neurites from the neural tube of Xenopus laevis in tissue culture. When presented with segmented somitic myoblasts or sheets of skin, spinal neurites grew selectively towards the somitic myoblasts. Neurites were not attracted specifically to somitic myoblasts from their own rostrocaudal level. A variable proportion of myoblasts from unsegmented caudal mesoderm differentiated and elongated in co-culture with neural tube and skin. These myoblasts also attracted neural outgrowths, but only if present in sufficient numbers. An agar slab containing medium conditioned by the presence of segmented myoblasts for 1 day attracted neurite outgrowths. A source of medium conditioned by the presence of undifferentiated, unsegmented myotomal mesoderm alone did not attract neurite outgrowths. Nerve growth factor (NGF) at a range of concentrations in the agar source (500-10,000 ng/ml) did not attract the earliest neurite outgrowths. It is concluded that the earliest skeletal myoblasts from Xenopus laevis embryos may attract neural outgrowths by releasing a soluble factor. Myoblasts may have to develop to the stage of somite segmentation before secretion of such an agent begins. The release of a myoblast-derived factor so early in development may assist directed nerve growth in vivo.

Myoblasts and notochord influence the orientation of somitic myoblasts from Xenopus laevis

The orientation of developing myoblasts extending a bipolar axis in the presence of explanted myoblasts or whole notochord has been studied in vitro. Myoblasts tended to elongate perpendicular to the lines of diffusion of substances from these tissues. A slow-release source of agar impregnated with medium conditioned by segmented somitic myoblast or notochord also caused myoblasts to elongate perpendicular to the lines of diffusion from the source. Medium conditioned by neural tube cells or unsegmented mesoderm cells did not influence the orientation of myoblasts. It is concluded that somites and notochord release diffusible substances in vitro which are capable of directing the orientation of developing myoblasts. In vivo, a somite-derived material could play a role in determining the direction of myoblast elongation in the presomitic mesoderm. An interaction between somite and notochord-derived secretions could influence the rotation of presomitic myoblasts to form a segmented somite.

BILATERAL NEOPLASTIC KIDNEY DISEASE, PULMONARY CYSTIC DISEASE, AND FETAL MACROSOMIA: A SPECTRUM OF DEVELOPMENTAL ABNORMALITIES

Three similar cases of bilateral neoplastic disease of the kidney were associated with congenital pulmonary cystic disease and fetal macrosomia. These cases are compared to several in the literature. We suggest that these three cases represent a spectrum of abnormal morphogenesis that affects both the kidney and the lung. Case 1 had bilateral multilocular cysts of the kidney in association with hamartomatous pulmonary cysts, This case is compared with Case 2 who had bilateral multilocular renal cysts, with one area of mesoblastic nephroma and multiple pulmonary cysts. These cases are compared to Case 3 who demonstrated markedly hyperplastic renomegaly with medullary dysplasia (similar to what is seen in the Beckwith-Wiedemann syndrome) in association with classical bilateral cystic adenomatoid malformation of the lungs. All three cases were overgrown at birth, and we suggest that these cases illustrate similarities in the development of kidneys and lungs. Embryologically the kidney and lung begin their development around the same time. During the 5th week of gestation, the ureteric bud invades the unsegmented mesoderm that becomes the metanephric system, and the lung bud invades the splanchnic mesoderm which provides the stimulus for its growth. The predominant pattern of a congenital kidney or lung neoplasm may reflect the timing of a prenatal neoplastic event.