Biomedical subjects

H W van Straaten

Publications and source records attributed to H W van Straaten.

At least 19 recordsLinked to original sources

PubMed2001

Curly tail: a 50-year history of the mouse spina bifida model.

This paper reviews 50 years of progress towards understanding the aetiology and pathogenesis of neural tube defects (NTD) in the curly tail (ct) mutant mouse. More than 45 papers have been published on various aspects of curly tail with the result that it is now the best understood mouse model of NTD pathogenesis. The failure of closure of the spinal neural tube, which leads to spina bifida in this mouse, has been traced back to a tissue-specific defect of cell proliferation in the tail bud of the E9.5 embryo. This cell proliferation defect results in a growth imbalance in the caudal region that generates ventral curvature of the body axis. Neurulation movements are opposed, leading to delayed neuropore closure and spina bifida, or tail defects. It is interesting to reflect that these advances have been achieved in the absence of information on the nature of the ct gene product, which remains unidentified. In addition to the principal ct gene, which maps to distal Chromosome 4, the curly tail phenotype is influenced by several modifier genes and by environmental factors. NTD in curly tail are resistant to folic acid, as is thought to be the case in 30% of human NTD, whereas they can be prevented by myo-inositol. These and other features of NTD in this system bear striking similarities to the situation in humans, making curly tail a model for understanding a sub-type folic acid-resistant human NTD.

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PubMed2001

Quantification and localisation of damage in rat muscles after controlled loading; a new approach to study the aetiology of pressure sores.

To obtain more insight in the aetiology of deep pressure sores, an animal model was developed to relate controlled external loading to local muscle damage. The tibialis anterior muscle (TA) and overlying skin of a rat were compressed between indentor and tibia. Loads of 10, 70 and 250kPa at skin surface were applied for 2 or 6h. During half of the 10 and 250kPa experiments interstitial fluid pressure (IFP) in the TA was measured. The TAs were excised 24h after load application. Both amount and location of damage were assessed by histological examination using a semi-automated image-processing program. In six of eleven loaded muscles damage was found. The damage was located from superficial to deep muscle tissue in a zone never exceeding the diameter of the indentor. The IFP measurements interfered with the occurrence of damage; application of 10 and 70kPa loads only caused damage when combined with IFP measurements, whereas IFP measurements increased damage at 250kPa loads. The results showed that the developed animal model can be used to provoke local damage by applying a controlled load and that the amount and location of damage can be assessed using the newly developed techniques.

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PubMed2001

Folate, homocysteine and neural tube defects: an overview.

Folate administration substantially reduces the risk on neural tube detects (NTD). The interest for studying a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate-dependent Hcy metabolism. Thus far, this has led to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies and also, in part, the protective effect of folate on NTD. Although the MTHFR polymorphisms are only moderate risk factors, population-wide they may account for an important part of the observed NTD prevalence.

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PubMed2000

Neurulation in the pig embryo.

Neurulation is based on a multitude of factors and processes generated both inside and outside the neural plate. Although there are models for a general neurulation mechanism, specific sets of factors and processes have been shown to be involved in neurulation depending on developmental time and rostro-caudal location at which neurulation occurred in the species under investigation. To find a common thread amongst these apparently divergent modes of neurulation another representative mammalian species, the pig, was studied here by scanning electron microscopy. The data are compared to a series of descriptions in other species. Furthermore, the relation of axial curvature and neural tube closure rate is investigated. In the pig embryo of 7 somites, the first apposition of the neural folds occurs at somite levels 5-7. This corresponds to closure site I in the mouse embryo. At the next stage the rostral and caudal parts of the rhombencephalic folds appose, leaving an opening in between. Therefore, at this stage four neuropores can be distinguished, of which the anterior and posterior ones will remain open longest. The two rhombencephalic closure sites have no counterpart in the mouse, but do have some resemblance to those of the rabbit. The anterior neuropore closes in three phases: (1) the dorsal folds slowly align and then close instantaneously, the slow progression being likely due to a counteracting effect of the mesencephalic flexure; (2) the dorso-lateral folds close in a zipper-like fashion in caudo-rostral direction; (3) the final round aperture is likely to close by circumferential growth. At the stage of 22 somites the anterior neuropore is completely closed. In contrast to the two de novo closure sites for the anterior neuropore in the mouse embryo, none of these were detected in the pig embryo. The posterior neuropore closes initially very fast in the somitic region, but this process almost stops thereafter. We suggest that the somites force the neural folds to elevate precociously. Between the stages of 8-20 somites the width of the posterior neuropore does not change, while the rate of closure gradually increases; this increase may be due to a catch-up of intrinsic neurulation processes and to the reduction of axial curvature. At the stage of 20-22 somites the posterior neuropore suddenly reduces in size but thereafter a small neuropore remains for 5 somite stages. The closure of the posterior neuropore is completed at the stage of 28 somites.

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PubMed1998

Neurulation in the rabbit embryo.

Among a broad range of factors and mechanisms involved in the complex process of neurulation a relationship between the curvature of the craniocaudal body axis and rate of neural tube closure has been proposed, but more examples and models are needed to further substantiate the existence of this relationship. This is particularly true for mammals, where marked differences in embryonic body curvature between species exist. The rabbit embryo has virtually no curvature during the main phase of neurulation and is therefore a suitable model, but neurulation is hardly documented in this species. In the present study, therefore, neural tube closure in the rabbit embryo is presented in detail by morphological and morphometrical parameters, as well as from scanning electron microscopic investigations. At the stages of 6-8 somites, the flat neural plate transforms into a V-shaped neural groove, beginning at the rhombo-cervical level. Between the stages of 8 and 9 somites, multiple closure sites occur simultaneously at three levels: at the incipient pros-mesencephalic transition, at the incipient mes-rhombencephalic transition, and at the level of the first pairs of somites. This results in four transient neuropores. The anterior and rhombencephalic neuropores close between the stages of 9-11 somites. The mesencephalic neuropore is very briefly present. The posterior neuropore is the largest and remains longest. Its tapered (cranial) portion closes fast within somite stages 9-10. Subsequently its wide (caudal) portion closes up to a narrow slit, but further closure slows down till full closure is achieved at the 22-somite stage. In comparing rabbit neurulation with that of chick and mouse, the sequence of multiple site closure resembles that of the mouse embryo, but other important aspects of neurulation resemble those of the chick embryo. In contrast to mouse and chick, no time lag between closure at the three closure sites in the rabbit was seen.

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PubMed1998

Reduced glucose consumption in the curly tail mouse does not initiate the pathogenesis leading to spinal neural tube defects.

At embryonic stages of neural tube closure, the mouse embryo exhibits a high rate of glycolysis with glucose as the main energy source. In the curly tail mouse, often used as model system for study of human neural tube defects, a delay in closure of the posterior neuropore (PNP) is proposed to be indirectly caused by a proliferation defect in the caudal region. Because glucose is important for proliferation, we tested glucose uptake in curly tail and control embryos, and in a BALB/c-curly tail recombinant strain. The structure and expression of Glut-1, a glucose transporter molecule that is abundantly present during those embryonic stages and that has been mapped in the region of the major curly tail gene, were also studied; however, no strain differences could be demonstrated. Glucose uptake was determined by measuring glucose depletion from the medium in long-term embryo cultures that encompassed the stages of PNP closure and by measuring accumulation of 3H-deoxyglucose in short-term cultures at the stages of early and final PNP closure. Both approaches indicated a reduced glucose uptake by curly tail and recombinant embryos. Surprisingly, the uptake per cell appeared normal, accompanied by a significantly lower DNA content of the mutant embryos. Therefore, it is unlikely that reduced cell proliferation is caused by a reduction in glucose supply during the pathogenesis of the defects in curly tail embryos. The reduced DNA content as well as the reduced glucose uptake per embryo are likely downstream effects of the aberrant proliferation pattern.

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PubMed1997

Initial closure of the mesencephalic neural groove in the chick embryo involves a releasing zipping-up mechanism.

According to a traditional viewpoint, initial closure of the anterior neural groove involves bilateral elevation of the edges of the neural plate, flattening of the midline area, subsequent convergence of the dorsal neural folds, and finally adhesion and fusion of the medial fold edges. In a transverse view, the shape of the neural groove thereby changes from V > U > toppled C > O. This sequence implicates that the neural groove is wide almost from its inception. In the present study, a new mechanism of initial closure is proposed, based on observations in living chick embryos and on light and scanning electron microscopic observations during neurulation in the presumptive mesencephalic region. The medial part of the neural plate invaginates in ventral direction. The walls of the arising neural groove appose, beginning in the depth, and make subsequent contact. During continued invagination the neural walls extend in ventral direction, the apposition/contact zone shifts in dorsal direction up to the neural folds and the neural walls separate ventrally, resulting in the incipient neural tube lumen. The mechanism is best compared with a zipping-up releasing model. In a transverse view, the shape of the neural groove changes from V > Y > I > O. While, according to the traditional view, the neural folds have to converge from a distance in order to contact each other, in the present mechanism the walls and folds are sequentially in contact by the ventro-dorsal zipping-up mechanism, thereby avoiding the possibility of mismatch of the neural folds. The above process is initiated over a considerable longitudinal distance along the neural plate, but only at the mesencephalic level does the dorsal shift of the contact zone become complete. At other levels of the neuraxis, the contact zone releases prematurely and the neural walls become widely separated well before their dorsal neural folds are in contact. These folds have to converge, therefore, in order to close, but their matching is facilitated by the alignment of the previously contacted neural folds at the mesencephalic level as well as by guidance underneath the vitelline membrane.

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PubMed1997

Spatio-temporal curvature pattern of the caudal body axis for non-mutant and curly tail mouse embryos during the period of caudal neural tube closure.

During the period of early organogenesis the mouse embryo has a curved body shape, which is thought to interact with ongoing developmental processes. Curly tail is a mouse mutant causing spina bifida, in which aberrant axial curvature is considered to be responsible for a delay in the closure of the posterior neuropore (PNP). Since detailed descriptions of axial curvature have never been made in either the normal or the mutant embryo, the onset and development of the aberrant axial curvature in the curly tail embryo are unknown. In the present study, axial curvature and segmental growth during closure of the PNP are described using circle segments at each somite level in two non-mutant mouse strains. Using the radius and angle of the segments as parameters, CD-1 and Balb/c mouse embryos showed maxima of curvature at the levels of the limb buds. Throughout development, a general axial unbending occurred that was due to a level-specific combination of general outgrowth and other factors. A marked additional decrease in the axial curvature was spatially and temporally related to the final closure of the PNP, indicating that this decrease of curvature facilities the final closure of the PNP. In the curly tail embryo the segment parameter radius was used to relate the axial curvature to an aberrant neural tube closure pattern. These embryos exhibited an enhanced curvature over the entire neuropore region as soon as a delay in the PNP closure could be distinguished. A steep decrease in curvature during final closure of the PNP did also occur, but at a more caudal level. Both the axial level of straightening and the rate of curvature were normalized at advanced developmental stages. The aberrant spatio-temporal curvature pattern in the curly tail mouse embryo indicates that both the rate of curvature and the axial level of unbending are important for a correct PNP closure.

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PubMed1996

Relationship between altered axial curvature and neural tube closure in normal and mutant (curly tail) mouse embryos.

Neural tube defects, including spina bifida, develop in the curly tail mutant mouse as a result of delayed closure of the posterior neuropore at 10.5 days of gestation. Affected embryos are characterized by increased ventral curvature of the caudal region. To determine whether closure of the neuropore could be affected by this angle of curvature, we experimentally enhanced the curvature of non-mutant embryos. The amnion was opened in 9.5 day embryos; after 20 h of culture, a proportion of the embryos exhibited a tightly wrapped amnion with enhanced curvature of the caudal region compared with the control embryos in which the opened amnion remained inflated. Enhanced curvature correlated with a higher frequency of embryos with an open posterior neuropore, irrespective of developmental stage within the range, 27-32 somites. Thus, within this somite range, caudal curvature is a more accurate determinant for normal spinal neurulation than the exact somite stage. Enhanced ventral curvature of the curly tail embryo correlates with an abnormal growth difference between the neuroepithelium and ventral structures (the notochord and hindgut). We experimentally corrected this imbalance by culturing under conditions of mild hyperthermia and subsequently determined whether the angle of curvature would also be corrected. The mean angle of curvature and length of the posterior neuropore were both reduced in embryos cultured at 40.5 degrees C by comparison with control embryos cultured at 38 degrees C. We conclude that the sequence of morphogenetic events leading to spinal neural tube defects in curly tail embryos involves an imbalance of growth rates, which leads to enhanced ventral curvature that, in turn, leads to delayed closure of the posterior neuropore.

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PubMed1995

Dietary methionine does not reduce penetrance in curly tail mice but causes a phenotype-specific decrease in embryonic growth.

The mouse mutation, curly tail, has incomplete penetrance and variable expression. Approximately 60% of the mice have a curly tail (CT), from which up to 20% may have lumbosacral spina bifida. Approximately 40% are normal, with a straight tail (ST). We tested whether L-methionine, which reduces the penetrance of neural tube defects in the Axd mouse mutant, has beneficial effects in the curly tail mutant. A single injection of L-methionine (200-1600 mg/kg body wt) on d 9 of pregnancy had no effect on the embryos, whereas there was a minor increase in penetrance at the highest dose. Chronic supplementation of L-methionine via the drinking water (1554 mg.kg body wt-1.d-1) did not shift penetrance. However, it decreased the weight of d 13 embryos from ST dams but not of those from CT dams. This phenotype-specific difference in response was evident and most unexpected. Mice from curly tail and other inbred strains were subjected to an L-methionine loading test and serum homocysteine assay. The different strains varied in their basal serum homocysteine concentrations, and they had proportionate significant increases after L-methionine loading. In CT and ST mice, basal serum homocysteine concentrations as well as the levels after loading were similar to each other and intermediate in the range of the mice tested. We conclude that L-methionine does not reduce penetrance in the curly tail mouse and that this strain reflects no derangement in L-methionine handling.

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PubMed1993

Raphe of the posterior neural tube in the chick embryo: its closure and reopening as studied in living embryos with a high definition light microscope.

Chick embryos cultured on a curved substratum show a transient enlargement of the posterior neuropore (PN), mimicking the temporary delay of PN closure as seen in the curly tail (ct) mouse mutant (van Straaten et al. [1993] Development 117:1163-1172). In the present study the PN enlargement in the chick embryo was investigated further with a high definition light microscope (HDmic), allowing high resolution viewing of living embryos in vitro. The temporary PN enlargement appeared due to considerable reopening of the raphe of the posterior neural tube, which was followed by reclosure after several hours. The raphe was subsequently studied in detail. It appeared very irregular, with small zones of apposed, open and fused neural folds. During closure, these raphe features shifted posteriorly. A distinct fusion sequence between surface epithelium and neuroepithelium was not seen. During experimental reopening of the raphe in vitro, small bridges temporarily arose, broke and disappeared quickly; they likely represented the first adhesion sites between the neural folds. More prominent adhesion sites partly detached, resulting in bridging filopodia-like connections; they probably represented the first anteroposterior locations of neural fold fusion. Our observations in the living chick embryo in vitro thus show that the caudal neural tube has an irregular raphe with few adhesion sites, which can be readily reopened. As a result of the irregularity, the PN does not close zipper-like, but button-like by forming multiple closure sites.

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PubMed1993

Evidence for a novel angiotensin II receptor involved in angiogenesis in chick embryo chorioallantoic membrane.

Angiotensin II acts as a growth factor in the cardiovascular system and has been implicated in angiogenesis. The existence of at least two types of angiotensin II receptors, the AT1 and the AT2 receptors, has been suggested by ligand binding studies. We used three different AT receptor antagonists to study the receptor mediating angiotensin II-induced angiogenesis in the chorioallantoic membrane (CAM) of the chick embryo. Angiotensin II caused pronounced angiogenesis of pre- and postcapillary vessels of 30-40%. This response could only be blocked by adding the peptidergic AT2 antagonist CGP-42112A. The nonpeptidergic AT2 antagonist PD123319 and AT1 antagonist losartan (DuP 753) were not effective. In addition, we used radioligand binding studies with a range of ligands to define the nature of the receptor. Our results show a high density of specific single class AT receptor with a total number of binding sites of 1,190 fmol/mg protein and an affinity constant for angiotensin II of 2.7 nM. The inhibitory concentrations (IC50) for CGP-42112A, PD 123319 and losartan were 724, > 100,000, and 59,000 nM, respectively. Our studies suggest that these binding sites act as receptors for angiotensin II-induced angiogenesis. Both functional and radioligand binding studies suggest that the receptor is different from the classical mammalian AT1 and AT2 receptors.

Allantois↗

PubMed1993

Intrinsic and extrinsic factors in the mechanism of neurulation: effect of curvature of the body axis on closure of the posterior neuropore.

Neurulation has been suggested to involve both factors intrinsic and extrinsic to the neuroepithelium. In the curly tail (ct) mutant mouse embryo, final closure of the posterior neuropore is delayed to varying extents resulting in neural tube defects. Evidence was presented recently (Brook et al., 1991 Development 113, 671-678) to suggest that enhanced ventral curvature of the caudal region is responsible for the neurulation defect, which probably originates from an abnormally reduced rate of cell proliferation affecting the hindgut endoderm and notochord, but not the neuroepithelium (Copp et al., 1988, Development 104, 285-295). This axial curvature probably generates a mechanical stress on the posterior neuropore, opposing normal closure. We predicted, therefore, that the ct/ct posterior neuropore should be capable of normal closure if the neuropore should be capable of normal closure if the neuroepithelium is isolated from its adjacent tissues. This prediction was tested by in vitro culture of ct/ct posterior neuropore regions, isolated by a cut caudal to the 5th from last somite. In experimental explants, the neuroepithelium of the posterior neuropore, together with the contiguous portion of the neural tube, were separated mechanically from all adjacent non-neural tissues. The posterior neuropore closed in these explants at a similar rate to isolated posterior neuropore regions of non-mutant embryos. By contrast, control ct/ct explants, in which the caudal region was isolated but the neuroepithelium was left attached to adjacent tissues, showed delayed neurulation. To examine further the idea that axial curvature may be a general mechanism regulating neurulation, we cultured chick embryos on curved substrata in vitro. Slight curvature of the body axis (maximally 1 degree per mm axial length), of either concave or convex nature, resulted in delay of posterior neuropore closure in the chick embryo. Both incidence and extent of closure delay correlated with the degree of curvature that was imposed. We propose that during normal embryogenesis the rate of neurulation is related to the angle of axial curvature, such that experimental alterations in curvature will have differing effects (either enhancement or delay of closure) depending on the angle of curvature at which neurulation normally occurs in a given species, or at a given level of the body axis.

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PubMed1992

Deceleration and acceleration in the rate of posterior neuropore closure during neurulation in the curly tail (ct) mouse embryo.

Curly tail (ct) is a mouse mutant producing spinal neural tube defects as a result of delayed closure of the posterior neuropore (PNP). The purpose of the present study was to determine in ct/ct embryos the time of onset of the delay in PNP closure, and the pattern of this closure, as well as to study the possibility that reopening of the neural tube occurs. Normal spinal neurulation was studied in non-mutant Swiss (Sw) embryos. In the latter, the average PNP length diminished steadily between the 7- and 25-somite stages, and then decreased more rapidly, indicating an acceleration of closure rate, until the 30- to 32-somite stage, when all PNPs closed. PNP width decreased steadily between the stages of 7 and 30 somites. In ct/ct embryos the average PNP length showed a slight increase between the stage of 23 to 28 somites, indicating a temporary deceleration of closure rate, and the range of PNP sizes increased markedly. This was followed by a decrease in PNP length until the 37-somite stage, indicating an acceleration of closure rate. From the stage of 32 somites onwards, the proportion of embryos with closed PNPs gradually increased to 90%. The population of ct/ct embryos was subdivided. Embryos with large PNPs showed a marked deceleration of closure rate during a period of 11 somite stages, followed by a brief but very high acceleration of closure rate.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1991

Development of floor plate, neurons and axonal outgrowth pattern in the early spinal cord of the notochord-deficient chick embryo.

The notochord is probably involved in the development of the neural tube. In this study, a fragment of caudal notochord was extirpated in ovo from chick embryos at 1.5 days of incubation. At 4.5 days a distinct notochord-deficient region at thoracolumbar level was found. Profound effects were seen, especially at the cranial site of this region. Somites were smaller than normal, or even not recognizable, and in some cases the myotomes were fused in the midline. The spinal cord appeared reduced in size and lacked a floor plate. The average amount of spinal cord neurons was 23% of the normal value, the cells being located circularly along the outer margin of the spinal cord, except for the roof plate. Axonal roots left the cord in the ventral midline only. Caudal to this site, neurons or floor plate cells were alternately present in the ventral spinal cord, and axonal roots left bilaterally. In a caudal direction, a normal morphology gradually reappeared. The possibility is discussed that reduction in spinal cord size and amount of neurons is a direct or indirect effect of the absence of the notochord, and that the sclerotome may be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed1989

Effect of the notochord on proliferation and differentiation in the neural tube of the chick embryo.

After implantation of a notochord fragment lateral to the neural tube in a 2-day chick embryo, at 4 days the ipsilateral neural tube half was increased in size and axons left the neural tube in a broad dorsoventral area (van Straaten et al. 1985). This enlargement appears to coincide with an increased area of AChE-positive basal plate neuroblasts, as determined with scan-cytophotometry. The effect was ipsilateral and local: clear effects were seen only when the implant was localized less than 80 microns from the neural tube and over 120 microns from the ventral notochord. In order to investigate the expected enhancement of proliferation, the mitotic density and the number of cells at the site of the implant at 3 days was determined and the mitotic index calculated. All three parameters showed an increase. It was concluded that the cell cycle was shorter in the implant area relative to the control area, at least during the third day. At 4 days the number of cells was still increased, predominantly in the basal plate. It appeared that the numerical increase was for the larger part due to neuroblasts. The synergism of two notochords thus resulted in enhancement of proliferation and differentiation in the neural tube. It is suggested that the notochord merely regulates and arranges the surrounding sclerenchymal cells, which are the effective cells in the regulation of neural tube development.

Acetylcholinesterase↗

PubMed1988

Effect of the notochord on the differentiation of a floor plate area in the neural tube of the chick embryo.

The role of a notochord fragment on the origin of an additional floor plate area in the neural tube is investigated by quantitative morphological methods. In 1.5 to 2 day chick embryos a notochordal fragment was implanted in close apposition to the lateral wall of the neural groove in the region between prospective wing and leg bud. At 4 days, adjacent to the implant a distinct area of the neural wall was present, which resembled the natural floor plate with respect to its thickness, the abluminal location of elongated nuclei and the absence of neuroblasts. The mitotic density of this area was reduced. This "additional floor plate" was distinct when the experiment was performed at 1.5 days but was hardly recognizable when it was carried out at 2 days. From these results it is concluded that a) the notochord induces floor plate like structures and diminishes proliferation, and b) that the period of floor plate induction by the notochord is very restricted.

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PubMed1987

Differentiation of gut endoderm in dependence of the notochord.

Presumptive intraembryonic endoderm, either isolated or together with adhering mesoderm, from 19-h chick embryos, was grafted to the coelom of 50-h host embryos. The viability of such grafts was low and endodermal differentiation was poor. In a second series the endoderm (with or without adhering mesoderm) was combined with a fragment of notochordal tissue from 48-60-h donor embryos. Then the recovery was much higher, notably after longer periods of in vivo culture. After 10 days of cultivation well-developed entero-endocrine (argyrophilic) cells were found among the regular enterocytes in both series.

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