Development of the human heart

In 2014, an extensive review discussing the major steps of cardiac development focusing on growth, formation of primary and chamber myocardium and the development of the cardiac electrical system, was published. Molecular genetic lineage analyses have since furthered our insight in the developmental origin of the various component parts of the heart, which currently can be unambiguously identified by their unique molecular phenotype. Moreover, genetic, molecular and cell biological analyses have driven insights into the mechanisms underlying the development of the different cardiac components. Here, we build on our previous review and provide an insight into the molecular mechanistic revelations that have forwarded the field of cardiac development. Despite the enormous advances in our knowledge over the last decade, the development of congenital cardiac malformations remains poorly understood. The challenge for the next decade will be to evaluate the different developmental processes using newly developed molecular genetic techniques to further unveil the gene regulatory networks operational during normal and abnormal cardiac development.     

Optical identification of calcium-dependent action potentials transiently expressed in the embryonic rat brainstem

Using multiple-site optical recording of transmembrane potential changes, we have found a new type of calcium-dependent action potential expressed transiently in the embryonic rat dorsal motor nucleus of the vagus nerve. Slice preparations with vagus nerve fibers attached were dissected from 12- to 16-day-old embryonic (E12–E16) rat brainstems, and they were stained with a voltage-sensitive merocyanine–rhodanine dye (NK2761). Electrical activities in response to vagal stimuli were optically recorded simultaneously from many sites using 1020- or 128-element photodiode array measuring systems. In brainstem preparations, two types of action potential-related optical signals were identified. One was detected from the dorsolateral region, and was related to sensory nerve activity (Type I). The other was detected from the dorsomedial region, and corresponded to the action potential in the dorsal motor nucleus of the vagus nerve (Type II). We found a difference in the ionic basis of the Type I vs Type II signals. The Type I signal was not altered in Ca²⁺-free bathing solution and was eliminated by tetrodotoxin, suggesting that the sensory nerve activity is mediated by Na⁺ currents. The Type II signal at early developmental stages (E12–E13, and some preparations in E14) was also independent of Ca²⁺. However, the Type II signal in later developmental stages (E15–E16, and some preparations in E14) did depend upon Ca²⁺: it was eliminated in Ca²⁺-free Ringer's solution, blocked by Cd²⁺, Ni²⁺ or Mn²⁺, and elicited in Sr²⁺-containing Ringer's solution, where CaCl₂ was replaced with SrCl₂. These results suggest that the cation which dominates the motoneuron action potential changes from Na⁺ to Ca²⁺ during development, and this change occurs around E14. With pharmacological analysis using Ca²⁺ channel blockers, we show that the Ca²⁺ channel mediating the motoneuron action potential is distinct from T-, L-, N-, P- or Q-type channels.

Because the vagal action potential in adult mammals is mainly mediated by Na⁺, we suggest that a Ca²⁺ action potential mediated by a new type of Ca²⁺ channel is expressed transiently in the rat dorsal motor nucleus of the vagus nerve at particular stages of development.     

A primer on investigating the role of the microbiome in brain and cognitive development

Incorporating information regarding the gut microbiota into psychobiological research promises to shed new light on how individual differences in brain and cognitive development emerge. However, the investigation of the gut-brain axis in development is still in its infancy and poses several challenges, including data analysis. Considering that the gut microbiome is an eco-system containing millions of bacteria, one needs to utilize a breadth of methodologies and data analytic techniques. The present review serves two purposes. First, this review will inform developmental psychobiology researchers about the emerging study of the gut-brain axis in development and second, this review will propose methodologies and data analytic strategies for integrating microbiome data in developmental research.     

Development of the origin of the coronary arteries, a matter of ingrowth or outgrowth?

Summary Inconsistencies still exist with regard to the exact mode of development of proximal coronary arteries and coronary orifices. In this regard 15 quail embryos were investigated using a monoclonal anti-endothelium antibody, enabling a detailed study of the development of endothelium-lined vasculature. Coronary orifices emerged at 7–9 days of incubation (Zacchei stages 24–26) and were invariably present at 10 days of incubation (Zacchei stage 27).We never observed more than 2 coronary orifices; these were always single in either of the facing sinuses of the aorta. A coronary orifice was always observed being connected to an already developed proximal coronary artery, which belonged to a peritruncal ring of coronary arterial vasculature. We did not find any coronary orifice without a connection to a proximal coronary artery. Moreover, at 7–9 days of incubation (Zacchei stages 24–26) we observed coronary arteries from the peritruncal ring penetrating the aortic media. In 2 specimen this coronary artery, with a lumen, was in contact with the still intact endothelial lining of the aorta.We conclude that coronary arteries do not grow out of the aorta, but grow into the aorta from the peritruncal ring of coronary arterial vasculature. This throws new light on normal and abnormal development of proximal coronary arteries and coronary orifices.     

Apoptosis in the cortex of the developing mouse kidney

Published levels of apoptosis in developing rat kidney (approximately 2.5%) seem large for a tissue with no obvious need for continual cell death. This paper examines the levels and patterns of apoptosis and mitosis in the cortical region of the developing metanephros of the mouse, the standard mammalian model embryo. Using confocal microscopy on specimens stained with propidium iodide to highlight nuclear morphology, optical sections of wholemount kidneys to a depth of approximately 50 microm were analysed and mitotic, apoptotic and interphase nuclei counted in the various compartments. Of the approximately 200 000 cells examined over E11.5-16.5, 2-3% were mitotic, confirming observations based on cryosections; the mitotic index peaked at E14.5, dropping to approximately 0.5% by P14. The mean apoptotic index during this period was 0.28%; this figure from wholemounts was approximately 10% of that earlier reported in cryosectioned rat kidneys. One possible explanation for the difference is that cryosectioning turns out to create small nuclear fragments that can stain strongly with propidium. Such fragments are not seen in wholemounts and do not stain with TUNEL. Wholemount mouse E11.5 tails and E16.5 lungs were also analysed and both their mitotic and their apoptotic indexes were similar to those in wholemount developing kidneys. These results show that the level of apoptosis in wholemount embryonic mouse kidney cortex is far less than previously reported in cryosectioned rat embryonic kidneys, and typical of that in other mouse embryonic tissues whose development seems not to require apoptosis.     

Glucocorticoid production in the chicken bursa and thymus

Glucocorticoid (GC) hormones play an important role in thymic T cell selection and in the development of autoimmune diseases. Previous studies have shown that the mammalian thymus itself is able to produce GC. In order to assess the importance of these findings in terms of the evolutionary development of the immune system, we investigated the functional presence of steroidogenic enzymes in primary lymphoid organs of chickens, which represent one of the best studied non-mammalian species. To this end, we attempted to demonstrate enzyme activities of the whole set of steroidogenic enzymes for the synthesis of GC in the bursa of Fabricius and the thymus. We isolated steroidogenic organelles from primary lymphoid tissues, incubated these with radioactive (precursor) steroids in vitro and visualized the resulting products by thin-layer chromatography. Our results show that the chicken bursa as well as the chicken thymus possesses all enzymes and cofactors required for GC production. The observation of GC production in an organ responsible for B cell selection and maturation is a further step in uncovering the yet ill-defined mechanism of B cell selection. These results provide the biochemical basis for the in situ hormonal effects, and underline the general importance of GC hormones on T and B lymphocyte development and selection.     

Development of the electrocorticogram during starvation in the rat

The effect of early malnutrition on the electrocorticogram (ECoG) of the rat was studied at eight different developmental stages. Gross observations of the ECoG records indicated that the normal ECoG activity developed from the fifth day; its characteristics consisted of low amplitude slow waves in the 1–15 cps range with a dominant frequency ranging from 6 to 8 cps. From the 7th to 11th postnatal days the proportion of fast activity in the 10–20 cps range progressively increased. This increment was associated with an augmentation in amplitude. The adult ECoG characteristics were achieved at the 18th postnatal day. In malnourished rats, a similar sequence of development was seen; compared to the controls, however, the malnourished rats showed an increment in the proportion of slow waves and a reduced voltage of ECoG up to 16 days when the differences disappeared. An average frequency analysis of the taped ECoG data indicated that in normally fed rats there was a rapid increment in the range and mode of frequency distribution from 5 to 16 days of age. From 18 to 30 days this increment followed a slowly ascending course, and by 30 days the averaged activity was similar to that of adults. Frequency distribution histograms of starved rats followed a similar sequence of development except that at all developmental ages (5–180 days) they exhibited slower frequencies.     

Some observations on the development of the human hyoid bone

Summary Investigations on the human hyoid bone in several developmental stages reveal that with the chondrification of the mesenchymal blastema a typical interzone between the body and the greater cornua is formed. This disc of closely packed blastemal cells, distinct and broad in the earlier stages, is reduced in thickness in the course of further development. In fetuses between 5 and 6 months old and in newborns the formation of joint cavities can be seen in some cases. In other cases, however, a small transverse line of cells persists between the two cartilaginous elements. These findings are interpreted as different developmental stages of a diarthrosis generally formed between the corpus and the cornu majus. The fact that in the adult the lesser horn is connected directly to the cornu majus and not to the body is confirmed by the embryological investigations reported in this study.Presented in part at the 72. Versammlung der Anatomischen Gesellschaft, Aachen, April 12–16, 1977Dedicated to Prof. Dr. R. Ortmann to his 65th Birthday     

Effects of an anti-TNF-alpha monoclonal antibody, administered throughout pregnancy and lactation, on the development of the macaque immune system

PROBLEM: The use of anti-TNF-alpha therapies during pregnancy and lactation on the development of the neonatal immune system has not been fully established. The purpose of this study was to evaluate whether treatment of macaques with an anti-TNF-alpha monoclonal antibody (golimumab) during pregnancy and lactation would result in defects in the developing immune system. METHOD OF STUDY: Pregnant macaques were treated with golimumab during pregnancy and lactation. Immune system development was evaluated by histopathology, lymphocyte subset analysis and functional challenging of the infant immune system (humoral immune response to KLH and TTX, and DTH skin reaction). RESULTS: In utero and postnatal exposure to golimumab had no effect on T and B cell populations in blood and lymphoid tissues and did not impair the ability of the infants to mount an immune response to antigen challenge. CONCLUSION: Treatment of pregnant macaques with golimumab throughout pregnancy and lactation did not affect the development and maturation of the immune system in the offspring.     

Genetic counseling: Growth of the profession and the professional

Growth of the profession of genetic counseling has gone hand-in-hand with professional development of individual genetic counselors. Genetic counseling has achieved most of the typical early milestones in the development of a profession. The profession is maturing at a time when the number of practitioners is predicted to vastly expand. The last two decades have seen a proliferation of genetic counselor roles and practice areas, and a distinct professional identity. It is likely that the next two decades will see an increase in educational paths, practice areas, and possibilities for professional advancement. How this maturation proceeds will be impacted by overall trends in healthcare, decisions made by international genetic counseling organizations, and thousands of individual decisions about career trajectories.     

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

Common lymphoid progenitors (CLPs) clonally produce both B- and T-cell lineages, but have little myeloid potential in vivo. However, some studies claim that the upstream lymphoid-primed multipotent progenitor (LMPP) is the thymic seeding population, and suggest that CLPs are primarily B-cell-restricted. To identify surface proteins that distinguish functional CLPs from B-cell progenitors, we used a new computational method of Mining Developmentally Regulated Genes (MiDReG). We identified Ly6d, which divides CLPs into two distinct populations: one that retains full in vivo lymphoid potential and produces more thymocytes at early timepoints than LMPP, and another that behaves essentially as a B-cell progenitor.     

Functional ontogeny in the central auditory pathway of the mongolian gerbil

Summary The 2-deoxyglucose (2-DG) autoradiographic technique was used to map functional activity in the central auditory system of the mongolian gerbil, throughout the period of functional onset. Uptake of 2-DG during exposure to 105 dB SPL wide band noise (WBN) was compared to silence in adults and in neonates at 12, 14, 16 and 18 days after birth (DAB). At 12 DAB, WBN exposure increased 2-DG uptake relative to silence only in the ventral cochlear nucleus. At 14 DAB, 2-DG uptake increased during WBN in the entire cochlear nuclear complex, superior olivary complex, and ventral nucleus of the lateral lemniscus. These stimulus-evoked increases in 2-DG uptake were at adult levels. However, little or no stimulus-evoked increase was seen in higher auditory nuclei at 14 DAB. By 16 DAB, 2-DG uptake also increased during WBN exposure in the dorsal nucleus of the lateral lemniscus, inferior colliculus and medial geniculate nucleus. By 18 DAB, WBN exposure produced increases in 2-DG uptake of medullary and pontine auditory nuclei which exceeded those seen in adults. At higher levels of the pathway, increases were comparable to those seen in adults. WBN-induced increases in 2-DG uptake observed in the cochlear nuclear and superior olivary complexes of neonates were comparable in all regions at all ages, even at 12 DAB. However, the 2-DG uptake increases observed at 16 and 18 DAB were appreciably greater in those regions of the inferior colliculus and medial geniculate nucleus which respond to high frequencies.Supported by grant 1R01 NS14945 from the NIH/NINCDS. Dr. A.F. Ryan is the recipient of Research Career Development Award 5K04 NS00176, also from the NIH/NINCDS     

Age-related differences in the chronic and acute response to cocaine in the rat

Behavioral sensitization is known to occur in adult animals after the chronic intermittent administration of cocaine. Dopaminergic pathways in the brain, such as the nigrostriatal and mesoaccumbens projections play a vital role in this phenomenon. These pathways are rudimentary in the 1st week of life, indicating that the developing animal may be unable to respond to cocaine in the same manner as an adult. In the present study, we report that the acute response to cocaine is remarkably similar between week-old and adult rats. Pups do not, however, show locomotor sensitization to acute cocaine after chronic cocaine administration as adults. © 1996 John Wiley & Sons, Inc.     

出生后大鼠海马结构的发育

目的：定量观察出生后大鼠海结构锥体细胞层和颗粒细胞层的发育。方法：用体视学原理定量分析。结果：阿蒙角锥体层,尤其是ＣＡ１区,其细胞层数逐渐减少。数密度、面数密度和体密度逐渐下降,平均体积逐渐增大。齿状回内臂逐渐延长,至Ｐ１４天接近成年水平。内外臂的细胞层数逐渐增加,至Ｐ９０天仍有增加趋势。在ＣＡ１、ＣＡ３、ＣＡ４区的锥体层和齿状回颗粒层中,数密度,面数密度和体密度按大小排序为：颗粒层〉ＣＡ１〉ＣＡ     

Gradual development of the ventral funiculus input to lumbar motoneurons in the neonatal rat

The in vitro brainstem–spinal cord preparation of newborn rats (0 to six-days-old) was used to investigate the development of pathways descending ventrally from the brainstem, which are important for the control of posture and locomotion. The ventral funiculus of the spinal cord was stimulated at the cervical (C1) level. Responses were recorded at the lumbar level from either motoneurons or ventral roots using intracellular microelectrodes or suction electrodes, respectively. Responses consisted of a pure excitation lasting 15 ms, followed by mixed excitatory/inhibitory responses. The inhibition was, at least partly, mediated by glycine. Excitatory amino acid transmission appears to be responsible for the excitation. The characteristics of the ventral funiculus-evoked postsynaptic potentials and ventral root potentials changed significantly with age. Their latency decreased whereas the slope and the area, measured over the first 15 ms, increased. The increase of the ventral funiculus input to motoneurons was slightly more pronounced than that of the monosynaptic dorsal root-evoked potentials from day 0 to day 4.

These data suggest a gradual arrival of ventral descending axons in the lumbar enlargement which may be responsible for the gradual acquisition of postural control that takes place during the first days after birth. This is a prerequisite for the development of the adult pattern of quadrupedal locomotion, with elevated trunk.     

早期干预对早产儿智力和运动发育影响的研究

目的探讨早期干预对早产儿智力和运动发育的影响。方法选取70例早产儿,随机分成实验组和对照组各35例,对实验组进行视觉、触觉、听觉和前庭功能早期干预,对照组常规新生儿科治疗护理,观察两组早产儿智力、运动发育指数。结果 3、6月,两组智力、运动发育指数无显著差异。12、18、24月,实验组智力发育指数呈明显上升趋势,运动发育指数在上升中18月时有波动,总体呈上升趋势;对照组智力、运动发育指数呈随月龄增加的趋势,但是上升幅度明显小于实验组,两组智力、运动发育指数差别有统计学意义。结论早期干预通过刺激机体的内分泌促进早产儿智力和运动能力发育。     

Mosaicism of the ventricular layer as the developmental basis of neocortical columnar organization. A 3H-thymidine autoradiographic study in newborn mice

Summary The ratio and local distribution of intensely and weakly labelled neurons as compared with unlabelled neurons were studied in newborn mice by means of autoradiography using ³H-thymidine injected at various embryonic ages. The distribution and migrational properties of intensely labelled neurons suggest that cells contributing to any given cortical layer are not generated simultaneously but in smaller units that correspond to cortical microcolumns. This implies a mosaicity in the genetic potential of the ventricular germinative layer.     

Genetic and epigenetic mechanisms in the early development of the vascular system

The cardiovascular system plays a critical role in vertebrate development and homeostasis. Vascular development is a highly organized sequence of events that requires the correct spatial and temporal expression of specific sets of genes leading to the development of a primary vascular network. There have been intensive efforts to determine the molecular mechanisms regulating vascular growth and development, and much of the rationale for this has stemmed from the increasing clinical importance and therapeutic potential of modulating vascular formation during various disease states.     

Metatarsal growth during the second trimester: a predictor of gestational age?

Metatarsal growth was studied in 780 human fetal metatarsal bones, crown-rump length ranging from 120 to 260 mm and gestational age ranging from 14 to 23 wk postconception. Total length, diaphyseal length and diameter were measured and statistical analysis performed. Means and standard deviations for each measurement were calculated at 1 wk intervals. These data were correlated with crown-rump length and gestational age and an equation was constructed in an attempt to predict gestational age.