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Optical mapping of the functional organization of the rat trigeminal nucleus: initial expression and spatiotemporal dynamics of sensory information transfer during embryogenesis.

We examined the functional organization of the rat trigeminal nuclear complex and its developmental dynamics using a multiple-site optical recording technique. Brainstem preparations were dissected from embryonic day 12 (E12)-E16 rat embryos, and stimulation was applied individually to the three branches of the trigeminal nerve (V1-V3). The action potential activity of presynaptic fibers was detected from E13, and the glutamate-mediated postsynaptic response was significantly observed from E15 on. At E14, the evoked signals usually consisted of only the action potential-related fast component. However, when extracellular Mg2+ was removed, a significant dl-2-amino-5-phosphonovaleric acid-sensitive slow component appeared. These results suggest that postsynaptic function mediated by NMDA receptors is latently generated as early as E14. The response area of the three branches of the trigeminal nerve showed some functional somatotopic organization, with the ophthalmic (V1) nerve area medially located and the mandibular (V3) nerve area laterally located. The center of the trigeminal nuclear complex in which the activity of neurons and synaptic function was greatest shifted caudally with development, suggesting that the functional architecture of the trigeminal nuclear complex is not fixed but changes dynamically during embryogenesis. By electron microscopy, we could not observe clear correlations between functional data and morphological information; when we surveyed E16 preparations, we could not identify typical synaptic structures between the 1,1'-dioctyldecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled trigeminal nerve terminals and the neurons in the trigeminal nuclear complex. This implies that postsynaptic function in the trigeminal nuclear complex is generated before the appearance of the morphological structure of conventional synapses.

Animals↗

Gene regulatory factors in pancreatic development.

The intensity of research on pancreatic development has increased markedly in the past 5 years, primarily for two reasons: we now know that the insulin-producing beta-cells normally arise from an endodermally derived, pancreas-specified precursor cell, and successful transplants of islet cells have been performed, relieving patients with type I diabetes of symptoms for extended periods after transplantation. Combining in vitro beta-cell formation from a pancreatic biopsy of a diabetic patient or from other stem-cell sources followed by endocrine cell transplantation may be the most beneficial route for a future diabetes therapy. However, to achieve this, a thorough understanding of the genetic components regulating the development of beta-cells is required. The following review discusses our current understanding of the transcription factor networks necessary for pancreatic development and how several genetic interactions coming into play at the earliest stages of endodermal development gradually help to build the pancreatic organ. Developmental Dynamics 229:176-200, 2004.

Animals↗

Turning heads: development of vertebrate branchiomotor neurons.

The cranial motor neurons innervate muscles that control eye, jaw, and facial movements of the vertebrate head and parasympathetic neurons that innervate certain glands and organs. These efferent neurons develop at characteristic locations in the brainstem, and their axons exit the neural tube in well-defined trajectories to innervate target tissues. This review is focused on a subset of cranial motor neurons called the branchiomotor neurons, which innervate muscles derived from the branchial (pharyngeal) arches. First, the organization of the branchiomotor pathways in zebrafish, chick, and mouse embryos will be compared, and the underlying axon guidance mechanisms will be addressed. Next, the molecular mechanisms that generate branchiomotor neurons and specify their identities will be discussed. Finally, the caudally directed or tangential migration of facial branchiomotor neurons will be examined. Given the advances in the characterization and analysis of vertebrate genomes, we can expect rapid progress in elucidating the cellular and molecular mechanisms underlying the development of these vital neuronal networks. Developmental Dynamics 229:143-161, 2004.

Animals↗

Genomic analysis of mouse retinal development.

The vertebrate retina is comprised of seven major cell types that are generated in overlapping but well-defined intervals. To identify genes that might regulate retinal development, gene expression in the developing retina was profiled at multiple time points using serial analysis of gene expression (SAGE). The expression patterns of 1,051 genes that showed developmentally dynamic expression by SAGE were investigated using in situ hybridization. A molecular atlas of gene expression in the developing and mature retina was thereby constructed, along with a taxonomic classification of developmental gene expression patterns. Genes were identified that label both temporal and spatial subsets of mitotic progenitor cells. For each developing and mature major retinal cell type, genes selectively expressed in that cell type were identified. The gene expression profiles of retinal Müller glia and mitotic progenitor cells were found to be highly similar, suggesting that Müller glia might serve to produce multiple retinal cell types under the right conditions. In addition, multiple transcripts that were evolutionarily conserved that did not appear to encode open reading frames of more than 100 amino acids in length ("noncoding RNAs") were found to be dynamically and specifically expressed in developing and mature retinal cell types. Finally, many photoreceptor-enriched genes that mapped to chromosomal intervals containing retinal disease genes were identified. These data serve as a starting point for functional investigations of the roles of these genes in retinal development and physiology.

Animals↗

[Morphometric study of the postnatal development of the human adrenal cortex].

Under study was the developmental dynamics of a number of morphometrical parameters of the adrenal cortex of man. The number of glandular cells in the organ was found to considerably decrease at late developmental periods, the size of nuclei in them diminished. These factors are considered to be responsible for the drop of functional activity of the adrenal cortex in elderly and senile age. The increase of the cell size during the growing of the organism is thought to be an important factor of the growth of the adrenal cortex of man.

Adolescent↗

Signal integration during development: insights from the Drosophila eye.

The Drosophila eye is a highly ordered epithelial tissue composed of approximately 750 subunits called ommatidia arranged in a reiterated hexagonal pattern. At higher resolution, observation of the constituent photoreceptors, cone cells, and pigment cells of the eye reveals a highly ordered mosaic of amazing regularity. This relatively simple organization belies the repeated requirement for spatially and temporally coordinated inputs from the Hedgehog (Hh), Wingless (Wg), Decapentaplegic (Dpp), JAK-STAT, Notch, and receptor tyrosine kinase (RTK) signaling pathways. This review will discuss how signaling inputs from the Notch and RTK pathways, superimposed on the developmental history of a cell, facilitate context-specific and appropriate cell fate specification decisions in the developing fly eye. Lessons learned from investigating the combinatorial signal integration strategies underlying Drosophila eye development will likely reveal cell-cell communication paradigms relevant to many aspects of invertebrate and mammalian development. Developmental Dynamics 229:162-175, 2004.

Animals↗

Relative expression of Slug, RhoB, and HNK-1 in the cranial neural crest of the early chicken embryo.

The neural crest constitutes a complex population of cells that originates at the edges of the neural plate of vertebrate embryos and gives rise to a high diversity of tissues and cell types. Molecular markers are very useful to identify cell populations, and in the case of the neural crest at early stages, many of them have been described. Here, we show a series of chicken embryos double labeled for several of the most commonly used crest markers that evidence the existence of different subpopulations. Slug is a very good marker for premigratory and early migratory cranial neural crest, RhoB labels delaminating cells and the very early migratory population, and the HNK-1 epitope is acquired in the migratory crest cells at a distance from the neural tube, with a significant proportion of the Slug-expressing migratory cells negative for HNK-1. The existence of these crest subpopulations should be considered when analyzing both wild-type embryos and the phenotype of experimentally manipulated chick embryos. Developmental Dynamics 229:136-139, 2004.

Animals↗

Universality in visual cortical pattern formation.

During ontogenetic development, the visual cortical circuitry is remodeled by activity-dependent mechanisms of synaptic plasticity. From a dynamical systems perspective this is a process of dynamic pattern formation. The emerging cortical network supports functional activity patterns that are used to guide the further improvement of the network's structure. In this picture, spontaneous symmetry breaking in the developmental dynamics of the cortical network underlies the emergence of cortical selectivities such as orientation preference. Here universal properties of this process depending only on basic biological symmetries of the cortical network are analyzed. In particular, we discuss the description of the development of orientation preference columns in terms of a dynamics of abstract order parameter fields, connect this description to the theory of Gaussian random fields, and show how the theory of Gaussian random fields can be used to obtain quantitative information on the generation and motion of pinwheels, in the two dimensional pattern of visual cortical orientation columns.

Animals↗

The cortex as a central pattern generator.

Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound similarities with neocortical circuits. CPGs can produce meaningful functional output in the absence of sensory inputs. Neocortical circuits could be considered analogous to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence. We find compelling evidence for this argument at the anatomical, biophysical, developmental, dynamic and pathological levels of analysis. Although it is possible that cortical circuits are particularly plastic types of CPG ('learning CPGs'), we argue that present knowledge about CPGs is likely to foretell the basic principles of the organization and dynamic function of cortical circuits.

Animals↗

Cell and fibronectin dynamics during branching morphogenesis.

Branching morphogenesis is a dynamic developmental process shared by many organs, but the mechanisms that reorganize cells during branching morphogenesis are not well understood. We hypothesized that extensive cell rearrangements are involved, and investigated cell migration using two-color confocal time-lapse microscopy to image cell and extracellular-matrix dynamics in developing salivary glands. We labeled submandibular salivary gland (SMG) epithelial cells with green fluorescent protein and matrix with fluorescent fibronectin. Surprisingly, we observed substantial, rapid and relatively random migration of individual epithelial cells during branching morphogenesis. We predicted that cell migration would decrease after formation of acini and, indeed, found that rapid cell movements do not occur in SMG from newborn mice. However, in embryonic SMG epithelial cells, we observed an absence of choreographed cell migration, indicating that patterned cell migration alone cannot explain the highly ordered process of branching morphogenesis. We therefore hypothesized a role for directional fibronection assembly in branching. Washout and pulse-chase experiments revealed that older fibronectin accumulates at the base of the clefts and translocates inwards as a wedge, with newer fibronectin assembling behind it. These findings identify a new mechanism for branching morphogenesis involving directional fibronectin translocation superimposed on individual cell dynamics.

Animals↗

Dynamics of antigenic membrane sites relating to cell aggregation in Dictyostelium discoideum.

Membrane interaction in aggregating cells of Dictyostelium discoideum can be blocked by univalent antibodies directed against specific membrane sites. Using a quantitative technique for measuring cell association, two classes of target sites for blocking antibodies were distinguished and their developmental dynamics studied. One class of these sites is specific for aggregation-competent cells, their quantity rising from virtually 0-level during growth, with a steep increase shortly before cell aggregation. The serological activity of these structures is species specific; they are not detectable in a nonaggregating mutant, but present in a revertant undergoing normal morphogenesis. Patterns of cell assembly in the presence of antibodies show that selective blockage of these membrane sites abolishes the preference for end-to-end association which is typical for aggregating cells. A second class of target sites is present in comparable quantities in particle fractions from both growth-phase and aggregation-competent cells. Blockage of these sites leads to aggregation patterns in which the side-by-side contacts of aggregating cells are abolished. The target sites of aggregation-inhibiting antibodies are suggested to be identical or associated with the molecular units of the cell membrane that mediate cell-to-cell contacts during aggregation. The results indicate that in one cell, two independent classes of contact sites can be simultaneously active.

Binding Sites, Antibody↗

A Pituitary cell type coexpressing messenger ribonucleic acid of proopiomelanocortin and the glycoprotein hormone alpha-subunit in neonatal rat and chicken: rapid decline with age and reappearance in vitro under regulatory pressure of corticotropin-releasing hormone in the rat.

Promiscuous hormone mRNA expression in the pituitary remains poorly understood. We examined by means of RT-PCR and immunostaining whether glycoprotein hormone alpha-subunit (alphaGSU) could be coexpressed with proopiomelanocortin (POMC) in vivo and under pressure of CRH in vitro. Cells coexpressing alphaGSU and POMC mRNA amounted to 2.6% of the cells in ex vivo rat pituitary at birth [postnatal d 1 (P1)], fell to much lower level at P14, and were undetectable in adulthood. In cultured pituitary aggregates of P14 rats, alphaGSU/POMC cells remained scarce but represented up to 6.6% after chronic treatment with CRH but not leukemia inhibitory factor. CRH was less effective in aggregates from P1 and adult rats. The total alphaGSU population ex vivo at P1 was two times smaller than at P14, but in culture it expanded 2.5 times, concomitantly with a reciprocal change in POMC cell abundance. Tpit transcripts were detected in POMC-only and alphaGSU/POMC cells but not in alphaGSU-only cells. Cells coexpressing alphaGSU and POMC mRNA were relatively abundant in P14 chicken pituitary and aggregate cultures, but occurrence was not affected by CRH. Immunostaining showed alphaGSU and POMC colocalization in sporadic cells in intact rat pituitary and CRH-treated cultures at P1 but not at P14 and adult age. The data demonstrate the occurrence of cells coexpressing alphaGSU and POMC in rat and chicken pituitary. The developmental dynamics of this cell population and its response to CRH in vitro in the rat suggest a relationship of these cells with the embryonic branching of the POMC and alphaGSU cell lineages and their mutually opposite developmental course during early postnatal life.

Aging↗

Genetic and environmental factors in health-related behaviors: studies on Finnish twins and twin families.

Family, twin and adoption studies have provided evidence for familial and genetic influences on individual differences in disease risk and in human behavior. Attempts to identify individual genes accounting for these differences have not been outstandingly successful to date, and at best, known genes account for only a fraction of the familiality of most traits or diseases. More detailed knowledge of the dynamics of gene action and of specific environmental conditions are needed. Twin and twin-family studies with multiple measurements of risk factors and morbidity over time can permit a much more detailed assessment of the developmental dynamics of disease risk and the unfolding of behavioral risk factors.

Adolescent↗

Early object relations into new objects.

Two strands of change are suggested by this review, one maturational, the other therapeutic or developmental (Hartmann and Kris, 1945). By "maturational" I mean to suggest energies that infuse the individual from earliest life in a manner that includes object relations, but for the healthy exercise of which object relations per se need not be of central and crucial importance. Within wide limits such energies may be delayed until growth conditions prevail without significant distortion of certain of the organism's ego functions. Therapeutic change is analogous to developmental change in that both involve the crucial presence of another to release energies. In therapeutic change these are energies that have been repressed beyond the reach of developmental dynamics. In everyday development crisis and synthesis alternate in conjunction with new and emerging objects to add to the psychological structures brought to the fore by maturation. In many instances, as we see with John, over time and in a less focussed manner, developmental changes can approximate therapeutic change and visa versa. Freud-Dann in their "experiment" pursued one line, in which the equipmental delay brought on by extremely adverse living circumstances was redressed by providing an interpersonally enriching, loving, developmentally facilitating milieu. The sketches of individual children and John's subsequent story provide a perspective into what becomes the stuff of growth and what remains the stuff of neurosis. The developmental reserves and ego resilience of these children were impressive but probably not extraordinary. Usual growth ensued as soon as they were provided with the rich soil of Bulldogs Bank instead of the desert sand of the Tereszin concentration camp. However, no one can escape such adverse circumstances without having taken in the stuff of neurosis. Affects and percepts that were not assimilatable or even available to consciousness at the time remain buried in the unconscious. Pain deprived of meaning is buried as neurosis. As we see in John's story, experience that cannot be integrated at the time is locked away from whatever developmental progression has occurred. Intolerable affects and ideas require particular circumstances of object relation and verbalization such as are found in the context of psychoanalysis and arrived at through psychoanalytic interpretation. Or, as in John's case, they may give way only slowly and irregularly over long stretches of time, when subjected to life experiences in the company of new object relations. Broadly stated, the Freud-Dann paper helps us to appreciate that there are several pathways of protection and growth in the ego that involve the discovery or construction of new objects. Family-romance fantasies are a common manifestation of new-object phenomena. Transitional object phenomena are also related. For some individuals at a particular time or over a span of time, providing the right circumstances for the resumption of maturational and developmental growth is all it takes to make them whole. Changes in the adaptive ego are sufficient to alleviate the conflicts stemming from the neurotic ego. For others, depending upon the degree of their neurotic impairment, or for the same individual under other circumstances, therapeutic change in the deepest sense demands the relatively unconditional presence of the interactive and interpreting other. Children of the storm who come in for shelter and warmth may thrive, but they also require a means of getting at the storm in their core that has been internalized as part of the ego's survival mechanism. What can be extracted from the poignant story of the Bulldogs Bank children about current child-analytic technique? The psychoanalytic piano now may be more formally conceptualized as having white as well as black keys. Most analyses, adult and child, have been conducted as though the "black keys"--pressure to mastery through repetition and its subsequent interpretation in relation to the transference--were the sole agents of therapeutic change. Reviewing maturation and development in relation to the resumption of psychological growth suggests that the provision of a beneficient environment, the "white keys," may lead to the resumption of maturational growth and change. The difference between the two modalities would be in the relative need for a significant other to bring about such change. Expanding on Hartmann and Kris, we can say that maturation requires a certain level of human stimulation and a supportive environment to unfold. At times in our work we encounter a psychoanalysis of and about maturation rather than primarily transference and interpretation. By and large the structure and functions of the ego that have been impeded in their exercise by traumatic circumstances in the environment are reactivated by a generalized holding environment rather than a relationship. In the practice of psychoanalysis this means that the child analyst may be more relaxed about the nonverbal play and relational aspects of the work; he need not fear that dynamics not captured in secondary process are lost to change. To the extent that the analysis provides an opportunity for maturational expression, growth will occur. When growth has been impeded by direct and significant interpersonal factors, the standard interpretative clarifications of defense, drive, and object relations in the context of removing the transference distortions regarding the analyst (and the world) are essential for recovery. Where the sequence of repetition through practice to mastery has become frozen by thwarting and stunting relationships, these potentially dead-end examples of neurotic object constancy must be played out on the "black keys." The amalgamation of the black of transference developments and the white of maturational emergence is paradigmatic for the discovery of new objects and new senses of self. In everyday life and analysis, maturation may lead to dramatic change that has hitherto been poorly identified and conceptualized. In child analysis, play is the medium for picking the lock of both arrested maturation and stultified development. Realizing that should permit the child analyst to engage more freely with the child in their own style of play without being overly concerned about the presence or absence of relational dynamic material. Non-dynamic play may not usually be defensive play, though it has often been misinterpreted as such. It may represent activity supporting renewed maturation--practice play in the service of memory, motility, or small or large motor function rather than in the service of the playful, repetitive externalization of threatening introjects. Dynamic play highlights the stagnant or emerging functions of the ego with regard to defense and affect management, which may then be interpreted using the play as key or using words as key to unlock the troubled relationship that is being dramatized. The analyst remains in a non-defensive stance, assigned by the analysand as audience or benign participant. Similarly, in adult analyses some individuals come pre-programmed not so much for interpretation as to discover the analyst as new object. They are in search of near psychobiological maturational closure on an object, already constituted in fantasy, that is respectful, attentive, objective, interested, and sometimes enlightening in their attempts at analytic understanding and developmental homeostasis. This phenomenon is akin to love at first sight, though without the flagrant libidinal romantic element. It occurs as the analytic narrative unfolds and the patient comes to a new sense of self, often around some developmental role or mix of roles, such as spouse, lover, mother, student, sibling, or worker. The point is that playing on the black and white keys of development and maturation leads to the appreciation of a psychoanalytic instrument that is at once more complex and yet easier to get music out of. And development continues from early objects to new objects. New and renewed understandings of analytic events necessarily guide the analyst in the timing of his traditional activities of attending, listening, talking, and relating. A contemporary surge of clinical understanding has led to a more active and informed relatedness on the part of the analyst that allows for a more compassionate approach to verbalization, whether with adults or children. We now know that not every word and every dynamic needs to be funneled through interpretation. The spontaneous powers for recovery that are stimulated by the analytic ground and the analytic process may come to be more accepted as a component of therapeutic gain. Appreciation of the balance of power between the verbal and nonverbal aspects of the analytic process in bringing about therapeutic change has increased. This has led to a greater parity of power and responsibility in the therapeutic alliance. The idea of a "tilted partnership" in which both members work for or against the powerful forces of the analytic process, or of a reciprocal relationship between analyst and analysand has become available to replace the former emphasis on the "tilted relationship." The analyst need no longer be so much in charge of the proceedings whether through deep interpretations of the unconscious or by obsessive attention to associational detail. The ongoing process of developing a body of theoretical and technical understanding that is both reliable and plastic demands an openness that at times flies in the face of the imperative needs of our patients and our profession for clinical confidence and certainty. The analytic clinician, part artist and part scientist, is forever struggling to balance the interminable task of culling new understanding from experience while imposing previously derived understandings that while sure are yet subject to changes stimulated by analytic experience. (ABSTRACT TRUNCATED)

Child↗

Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex.

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

Humans↗

Effect of experimental hyperphenylalaninemia on the postnatal rat brain.

The molecular mechanism of the disturbance of brain development caused by phenylketonuria remains mostly unknown. We have studied three molecular markers that reflect the development of neurons, glia and the extracellular matrix of the postnatal rat brain in an animal model of hyperphenylalaninemia, in order to elucidate the possible mechanism by which increased phenylalanine influences brain development. The content of NCAM, GFAP and hyaluronate-binding activity were compared in cerebellum and telencephalon of normal rats and those subjected to high phenylalanine. No statistically significant changes were found in telencephalon when experimental animals were compared to controls. In the hyperphenylalaninemic cerebellum, the developmental dynamic of NCAM content (represented by two peaks at about postnatal days 5 and 22 during normal development) is dramatically altered. The GFAP content in the cerebellum of treated rats exceeded those in controls significantly during late developmental stages (postnatal days 28-35). Hyaluronate-binding activity in the extracellular protein fraction from treated rat cerebellum was increased compared to normal rat at the early stages of development only (postnatal day 7). These results suggest that high serum phenylalanine may lead to permanent brain dysfunction through a disturbance of a wide range of developmental events.

Animals↗

Identification of neural crest competence territory: role of Wnt signaling.

In recent years, research on neural crest induction has allowed the identification of several molecules as candidates for neural crest inducers. Although many of these molecules have the ability to induce neural crest in different assays, a general mechanism of neural crest induction that includes a description of the tissues that produce the inductive signals and the time and steps in which this process takes place remains elusive. To better understand the mechanism of neural crest induction, we developed an assay that has been used previously by Nieuwkoop to study anterior-posterior pattern of the neural plate. Folds of competent ectoderm were implanted in different positions of a young neurula embryo, and the induction of neural crest was analyzed using the expression of the neural crest marker Xslug. We identified a very localized region of the early neurula where it is possible to get neural crest induction, whereas all of the regions tested showed a clear induction of the neural plate marker Xsox2. These results indicate that there is a region in the embryo with the appropriate combination of signals needed to induce neural crest cells; we called this region the neural crest competence territory. In addition, our results show that neural crest induction is always accompanied by neural plate induction, but there are many cases where neural plate was induced without neural crest. These results support the model in which the neural crest is induced by an interaction between neural plate and epidermis, but they also suggest that additional signals are required. By making grafts of different sizes and implanting them in the epidermis or the neural plate, we concluded that one of the inductive signals is produced in the dorsal region of the embryo and travels into the ectoderm. Finally, by performing gain- and loss-of-function of Wnt signaling experiments, we show that this pathway plays an important role not only in neural crest induction but also in the specification of the neural crest competence territory. Developmental Dynamics 229:109-117, 2004.

Animals↗

[Histogenesis of the thymus gland normally and under a change in the level of sympathetic mediation].

Under study was the dynamics of the ultrastructure of the reticular epithelium and lymphocytes of the thymus in postnatal ontogenesis of Balb/c mice. Special attention was given to secretory granules, vacuoles, folliculoid structures, intercellular contacts and cytoplasmic communications (bridges). In parallel the developmental dynamics of the capillary ultrastructure and the state of the adrenergic innervation apparatus were studied. The morphological data are compared with the functional dynamics of the thymus. The postnatal dynamics of means of the transmission of immunological information in the thymus was found. No adrenergic innervation was shown to be present in the thymus of newborns. The role of this mediation as a factor of thymus morphogenesis was confirmed.

Age Factors↗