A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo.
Morphogenesis depends on the precise control of basic cellular processes such as cell proliferation and differentiation. Wnt5a may regulate these processes since it is expressed in a gradient at the caudal end of the growing embryo during gastrulation, and later in the distal-most aspect of several structures that extend from the body. A loss-of-function mutation of Wnt5a leads to an inability to extend the A-P axis due to a progressive reduction in the size of caudal structures. In the limbs, truncation of the proximal skeleton and absence of distal digits correlates with reduced proliferation of putative progenitor cells within the progress zone. However, expression of progress zone markers, and several genes implicated in distal outgrowth and patterning including Distalless, Hoxd and Fgf family members was not altered. Taken together with the outgrowth defects observed in the developing face, ears and genitals, our data indicates that Wnt5a regulates a pathway common to many structures whose development requires extension from the primary body axis. The reduced number of proliferating cells in both the progress zone and the primitive streak mesoderm suggests that one function of Wnt5a is to regulate the proliferation of progenitor cells. (+info
Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine.
Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. One conclusion of these studies was that when low- and high-intensity stimuli induce responses of similar magnitude in nociceptive neurons, low-intensity stimuli must be as painful as the high-intensity stimuli. The present study investigates in anesthetized rats the significance of the changes in the responses of central trigeminal neurons (i.e., in nucleus caudalis) by correlating them with the occurrence and type of the simultaneously recorded cardiovascular responses. Before chemical stimulation of the dura, simultaneous increases in neuronal firing rates and blood pressure were induced by dural indentation with forces >/= 2.35 g and by noxious cutaneous stimuli such as pinching the skin and warming > 46 degrees C. After chemical stimulation, similar neuronal responses and blood pressure increases were evoked by much smaller forces for dural indentation and by innocuous cutaneous stimuli such as brushing the skin and warming it to >/= 43 degrees C. The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine. (+info
Otx expression during lamprey embryogenesis provides insights into the evolution of the vertebrate head and jaw.
Agnathan or jawless vertebrates, such as lampreys, occupy a critical phylogenetic position between the gnathostome or jawed vertebrates and the cephalochordates, represented by amphioxus. In order to gain insight into the evolution of the vertebrate head, we have cloned and characterized a homolog of the head-specific gene Otx from the lamprey Petromyzon marinus. This lamprey Otx gene is a clear phylogenetic outgroup to both the gnathostome Otx1 and Otx2 genes. Like its gnathostome counterparts, lamprey Otx is expressed throughout the presumptive forebrain and midbrain. Together, these results indicate that the divergence of Otx1 and Otx2 took place after the gnathostome/agnathan divergence and does not correlate with the origin of the vertebrate brain. Intriguingly, Otx is also expressed in the cephalic neural crest cells as well as mesenchymal and endodermal components of the first pharyngeal arch in lampreys, providing molecular evidence of homology with the gnathostome mandibular arch and insights into the evolution of the gnathostome jaw. (+info
Expression and developmental regulation of the Hydra-RFamide and Hydra-LWamide preprohormone genes in Hydra: evidence for transient phases of head formation.
Hydra magnipapillata has three distinct genes coding for preprohormones A, B, and C, each yielding a characteristic set of Hydra-RFamide (Arg-Phe-NH2) neuropeptides, and a fourth gene coding for a preprohormone that yields various Hydra-LWamide (Leu-Trp-NH2) neuropeptides. Using a whole-mount double-labeling in situ hybridization technique, we found that each of the four genes is specifically expressed in a different subset of neurons in the ectoderm of adult Hydra. The preprohormone A gene is expressed in neurons of the tentacles, hypostome (a region between tentacles and mouth opening), upper gastric region, and peduncle (an area just above the foot). The preprohormone B gene is exclusively expressed in neurons of the hypostome, whereas the preprohormone C gene is exclusively expressed in neurons of the tentacles. The Hydra-LWamide preprohormone gene is expressed in neurons located in all parts of Hydra with maxima in tentacles, hypostome, and basal disk (foot). Studies on animals regenerating a head showed that the prepro-Hydra-LWamide gene is expressed first, followed by the preprohormone A and subsequently the preprohormone C and the preprohormone B genes. This sequence of events could be explained by a model based on positional values in a morphogen gradient. Our head-regeneration experiments also give support for transient phases of head formation: first tentacle-specific preprohormone C neurons (frequently associated with a small tentacle bud) appear at the center of the regenerating tip, which they are then replaced by hypostome-specific preprohormone B neurons. Thus, the regenerating tip first attains a tentacle-like appearance and only later this tip develops into a hypostome. In a developing bud of Hydra, tentacle-specific preprohormone C neurons and hypostome-specific preprohormone B neurons appear about simultaneously in their correct positions, but during a later phase of head development, additional tentacle-specific preprohormone C neurons appear as a ring at the center of the hypostome and then disappear again. Nerve-free Hydra consisting of only epithelial cells do not express the preprohormone A, B, or C or the LWamide preprohormone genes. These animals, however, have a normal phenotype, showing that the preprohormone A, B, and C and the LWamide genes are not essential for the basic pattern formation of Hydra. (+info
The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals.
Embryological and genetic evidence indicates that the vertebrate head is induced by a different set of signals from those that organize trunk-tail development. The gene cerberus encodes a secreted protein that is expressed in anterior endoderm and has the unique property of inducing ectopic heads in the absence of trunk structures. Here we show that the cerberus protein functions as a multivalent growth-factor antagonist in the extracellular space: it binds to Nodal, BMP and Wnt proteins via independent sites. The expression of cerberus during gastrulation is activated by earlier nodal-related signals in endoderm and by Spemann-organizer factors that repress signalling by BMP and Wnt. In order for the head territory to form, we propose that signals involved in trunk development, such as those involving BMP, Wnt and Nodal proteins, must be inhibited in rostral regions. (+info
Goosecoid and mix.1 repress Brachyury expression and are required for head formation in Xenopus.
The Xenopus homologue of Brachyury, Xbra, is expressed in the presumptive mesoderm of the early gastrula. Induction of Xbra in animal pole tissue by activin occurs only in a narrow window of activin concentrations; if the level of inducer is too high, or too low, the gene is not expressed. Previously, we have suggested that the suppression of Xbra by high concentrations of activin is due to the action of genes such as goosecoid and Mix.1. Here, we examine the roles played by goosecoid and Mix.1 during normal development, first in the control of Xbra expression and then in the formation of the mesendoderm. Consistent with the model outlined above, inhibition of the function of either gene product leads to transient ectopic expression of Xbra. Such embryos later develop dorsoanterior defects and, in the case of interference with Mix.1, additional defects in heart and gut formation. Goosecoid, a transcriptional repressor, appears to act directly on transcription of Xbra. In contrast, Mix.1, which functions as a transcriptional activator, may act on Xbra indirectly, in part through activation of goosecoid. (+info
MIRD Pamphlet No. 15: Radionuclide S values in a revised dosimetric model of the adult head and brain. Medical Internal Radiation Dose.
Current dosimetric models of the brain and head lack the anatomic detail needed to provide the physical data necessary for suborgan brain dosimetry. During the last decade, several new radiopharmaceuticals have been introduced for brain imaging. The marked differences of these tracers in tissue specificity within the brain and their increasing use for diagnostic studies support the need for a more anthropomorphic model of the human brain and head for use in estimating regional absorbed dose within the brain and its adjacent structures. METHODS: A new brain model has been developed that includes eight subregions: the caudate nuclei, the cerebellum, the cerebral cortex, the lateral ventricles, the lentiform nuclei, the thalami, the third ventricle and the white matter. This brain model is incorporated within a total revision of the head model presented in MIRD Pamphlet No. 5 Revised. Modifications include the addition of the eyes, the teeth, the mandible, an upper facial region, a neck region and the cerebrospinal fluid within both the cranial and spinal regions. RESULTS: Absorbed fractions of energy for photon and electron sources located in 14 source regions within the new model were calculated using the EGS4 Monte Carlo radiation transport code for particles in the energy range 10 keV-4 MeV. These absorbed fractions were then used along with radionuclide decay data to generate S values for 24 radionuclides that are used in clinical or investigational studies of the brain, 12 radionuclides that localize within the cranium and spinal skeleton and 12 radionuclides that selectively localize in the thyroid gland. CONCLUSION: A substantial revision to the dosimetric model of the adult head and brain originally published in MIRD Pamphlet No. 5 Revised is presented. This revision supports suborgan brain dosimetry for a variety of radiopharmaceuticals used in neuroimaging. Dose calculations for the neuroimaging agent 1231-tropane provide an example of the new model and yield mean brain doses that are consistent with published values. However, the absorbed dose to subregions within the brain such as the caudate and lentiform nuclei may exceed the average brain dose by a factor of up to 5. (+info
Myotube heterogeneity in developing chick craniofacial skeletal muscles.
Avian skeletal muscles consist of myotubes that can be categorized according to contraction and fatigue properties, which are based largely on the types of myosins and metabolic enzymes present in the cells. Most mature muscles in the head are mixed, but they display a variety of ratios and distributions of fast and slow muscle cells. We examine the development of all head muscles in chick and quail embryos, using immunohistochemical assays that distinguish between fast and slow myosin heavy chain (MyHC) isoforms. Some muscles exhibit the mature spatial organization from the onset of primary myotube differentiation (e.g., jaw adductor complex). Many other muscles undergo substantial transformation during the transition from primary to secondary myogenesis, becoming mixed after having started as exclusively slow (e.g., oculorotatory, neck muscles) or fast (e.g., mandibular depressor) myotube populations. A few muscles are comprised exclusively of fast myotubes throughout their development and in the adult (e.g., the quail quadratus and pyramidalis muscles, chick stylohyoideus muscles). Most developing quail and chick head muscles exhibit identical fiber type composition; exceptions include the genioglossal (chick: initially slow, quail: mixed), quadratus and pyramidalis (chick: mixed, quail: fast), and stylohyoid (chick: fast, quail: mixed). The great diversity of spatial and temporal scenarios during myogenesis of head muscles exceeds that observed in the limbs and trunk, and these observations, coupled with the results of precursor mapping studies, make it unlikely that a lineage based model, in which individual myoblasts are restricted to fast or slow fates, is in operation. More likely, spatiotemporal patterning of muscle fiber types is coupled with the interactions that direct the movements of muscle precursors and subsequent segregation of individual muscles from common myogenic condensations. In the head, most of these events are facilitated by connective tissue precursors derived from the neural crest. Whether these influences act upon uncommitted, or biased but not restricted, myogenic mesenchymal cells remains to be tested. (+info