The role of neurotrophins during successive stages of sensory neuron development

Neurotrophins comprise a family of basic homodimeric proteins. The isolation of the first two neurotrophins, nerve growth factor and brain-derived neurotrophic factor, was based on the ability of these proteins to promote the survival of embryonic neurons. However, the identification of additional neurotrophins by homology screening together with recent work on these proteins has shown that neurotrophins do more than just regulate neuronal survival. Neurotrophins influence the proliferation and differentiation of neuron progenitor cells and regulate the expression of several differentiated traits of neurons throughout life. Moreover, the influence of neurotrophins on survival is more complex than originally thought; some neurons switch their survival requirements from one set of neurotrophins to another during development and several neurotrophins may be involved in regulating the survival of a population of neurons at any one time. Most of what is known of the developmental physiology of neurotrophins has come from studying neurons of the peripheral nervous system. Quite apart from the accessibility of these neurons and their progenitor cell populations, investigation of the actions of neurotrophins on several well-characterised populations of sensory neurons has permitted the age-related changes in the effects of neurotrophins to be interpreted in the appropriate developmental context. In this review I provide a chronological account of the action of neurotrophins in neuronal development with special reference to sensory neurons.     

The role of sensory input in motor neuron sprouting control

Primary sensory neurons project to motor neurons directly or through interneurons and affect their activity. In our previous paper we showed that intramuscular sprouting can be affected by changing the sensory synaptic input to motor neurons. In this work, motor axon sprouting within a peripheral nerve (extramuscular sprouting) was induced by nerve injury at such a distance from muscle so as not to allow nerve-muscle trophic interactions. Two different procedures were carried out: (1) sciatic nerve crush and (2) sciatic nerve crush with homosegmental ipsilateral L3-L5 dorsal rhizotomy. The number of regenerating motor axons innervating extensor digitorum longus muscle was determined by in vivo muscle tension recordings and an index of their individual conduction rate was obtained by in vitro intracellular recordings of excitatory postsynaptic end-plate potentials in muscle fibers. The main findings were: (1) there are more regenerated axons distally from the lesion than parent axons proximally to the lesion (sprouting at the lesion); (2) sprouting at the lesion was negatively affected by homosegmental ipsilateral dorsal rhizotomy; (3) the number of motor axons innervating extensor digitorum longus muscle extrafusal fibers counted proximally to the lesion increased following nerve injury and regeneration but this did not occur when sensory input was lost. A transient innervation of extrafusal fibers by gamma motor neurons may explain the increase of motor axons counted proximally to the lesion.     

The role of sensory input in motor neuron sprouting control

Primary sensory neurons project to motor neurons directly or through interneurons and affect their activity. In our previous paper we showed that intramuscular sprouting can be affected by changing the sensory synaptic input to motor neurons. In this work, motor axon sprouting within a peripheral nerve (extramuscular sprouting) was induced by nerve injury at such a distance from muscle so as not to allow nerve-muscle trophic interactions. Two different procedures were carried out: (1) sciatic nerve crush and (2) sciatic nerve crush with homosegmental ipsilateral L3-L5 dorsal rhizotomy. The number of regenerating motor axons innervating extensor digitorum longus muscle was determined by in vivo muscle tension recordings and an index of their individual conduction rate was obtained by in vitro intracellular recordings of excitatory postsynaptic end-plate potentials in muscle fibers. The main findings were: (1) there are more regenerated axons distally from the lesion than parent axons proximally to the lesion (sprouting at the lesion); (2) sprouting at the lesion was negatively affected by homosegmental ipsilateral dorsal rhizotomy; (3) the number of motor axons innervating extensor digitorum longus muscle extrafusal fibers counted proximally to the lesion increased following nerve injury and regeneration but this did not occur when sensory input was lost. A transient innervation of extrafusal fibers by &#110 motor neurons may explain the increase of motor axons counted proximally to the lesion.     

Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis

More than a decade of research has shown that Sertoli cell proliferation is regulated by thyroid hormone. Neonatal hypothyroidism lengthens the period of Sertoli cell proliferation, leading to increases in Sertoli cell number, testis weight, and daily sperm production (DSP) when euthyroidism is re-established. In contrast, the neonatal Sertoli cell proliferative period is shortened under hyperthyroid conditions, but the mechanism by which thyroid hormone is able to negatively regulate Sertoli cell proliferation has been unclear. Recent progress in the understanding of the cell cycle has provided the opportunity to dissect the molecular targets responsible for thyroid-hormone-mediated effects on Sertoli cell proliferation. In this review, we discuss recent results indicating a critical role for the cyclin-dependent kinase inhibitors (CDKI) p27^Kip1 and p21^Cip1 in establishing Sertoli cell number, testis weight, and DSP, and the ability of thyroid hormone to modulate these CDKIs. Based on these recent results, we propose a working hypothesis for the way in which thyroid hormone regulates the withdrawal of the cell cycle by controlling CDKI degradation. Finally, although Sertoli cells have been shown to have two biologically active thyroid hormone receptor (TR) isoforms, TRα1 and TRβ1, experiments with transgenic mice lacking TRα or TRβ illustrate that only one TR mediates thyroid hormone effects in neonatal Sertoli cells. Although significant gaps in our knowledge still remain, advances have been made toward appreciation of the molecular sequence of events that occur when thyroid hormone stimulates Sertoli cell maturation. We gratefully acknowledge the support of this work by the NIH, USDA, the University of Illinois, the Lalor Foundation, and the Thanis A. Field Endowment at the University of Illinois. D.R. Holsberger was supported by postdoctoral fellowships from the Lalor Foundation and Reproductive Biology Research Training Program (NIH grant T32 HD07028), University of Illinois at Urbana–Champaign.     

The role of succinic acid in neuron reaction to synaptic activation

It has been shown on Retzius neuron of the leech that after preintroduction of sodium succinate the reaction to synaptic stimulation expressed in increased frequency of the impulse activity proceeds more intensively than in the norm. In connection with the fact that against the background of succinate effect reaction to acetylcholine increases it is suggested that this very mediator is responsible for slower decrease of the impulse activity frequency at synaptic activation.     

The role of Thr5 in human neuron growth inhibitory factor

GIF, a member of the metallothionein (MT) family (assigned as MT3), is a neuron growth inhibitory factor that inhibits neuron outgrowth in Alzheimer’s disease. The conserved Thr5 is one of the main differences between GIF and other members in the MT family. However, natural sheep GIF has an unusual Ala5, casting doubt on the role of common Thr5. We constructed a series of human GIF mutants at site 5, and characterized their biochemical properties by UV spectroscopy, circular dichroism spectroscopy, EDTA reaction, 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) reaction, and pH titration. Their inhibitory activity toward neuron survival and neurite extension was also examined. Interestingly, the T5A mutant exhibited distinct metal thiolate activity in the EDTA and DTNB reactions, and also lost its bioactivity. Meanwhile, the T5S mutant had similar biochemical properties and biological activity as wild-type human GIF, indicating the hydroxyl group on the Thr5 was critical to the bioactivity of human GIF. We suggest the hydroxyl group in human GIF may help stabilize the biologically active conformation. On the other hand, lack of the hydroxyl group in sheep GIF may be partially compensated by its abnormal structure.Bin Cai and Qi Zheng contributed equally to this work.     

The role of thyroid hormones during the development of eye pigmentation in the Pacific bluefin tuna (Thunnus orientalis)

Thyroid hormones (THs) are essential for the embryonic and post-embryonic development of fish. We studied the role of THs during the early, post-embryonic, development of Pacific bluefin tuna. Embryos were treated with L-thyroxine (T(4)) or the anti-thyroid drug methimazole (MMI), and reared in microtitre plates for 3 days. Immersion in MMI, but not T(4), led to retardation of retinal pigment epithelium (RPE) pigmentation 3 days post-hatching (dph). Concurrent immersion in T(4) and MMI had no effect of RPE pigmentation. We also measured the expression of TRalphaA, TRalphaB, and TRbeta mRNA using real-time RT-PCR. Treatment with MMI significantly reduced TRbeta mRNA expression. Taken together these results suggest that the development of RPE pigmentation is mediated by TH, most likely via TRbeta.     

A role of unliganded thyroid hormone receptor in postembryonic development in Xenopus laevis

A fascinating feature of thyroid hormone (T3) receptors (TR) is that they constitutively bind to promoter regions of T3-response genes, providing dual functions. In the presence of T3, TR activates T3-inducible genes, while unliganded TR represses these same genes. Although this dual function model is well demonstrated at the molecular level, few studies have addressed the presence or the role of unliganded TR-induced repression in physiological settings. Here, we analyze the role of unliganded TR in Xenopus laevis development. The total dependence of amphibian metamorphosis upon T3 provides us a valuable opportunity for studying TR function in vivo. First, we designed a dominant negative form of TR-binding corepressor N-CoR (dnN-CoR) consisting of its receptor interacting domain. We confirmed its dominant negative activity by showing that dnN-CoR competes away the binding of endogenous N-CoR to unliganded TR and relieves unliganded TR-induced gene repression in frog oocytes. Next, we overexpressed dnN-CoR in tadpoles through transgenesis and analyzed its effect on gene expression and development. Quantitative RT-PCR revealed significant derepression of T3-response genes in transgenic animals. In addition, transgenic tadpoles developed faster than wild type siblings, with an acceleration of as much as 7 days out of the 30-day experiment. These data thus provide in vivo evidence for the presence and a role of unliganded TR-induced gene repression in physiological settings and strongly support our earlier model that unliganded TR represses T3-response genes in premetamorphic tadpoles to regulate the progress of development.     

The role of surgery in the management of thyroid cancer.

This is a review of one surgeon''s personal experience with 85 patients with thyroid cancer treated over a 20-year period. The data confirm that for papillary thyroid tumours, with rare exceptions, the prognosis is excellent. Anaplastic lesions, however, are consistently lethal. Follicular carcinoma and medullary carcinoma fall between these extremes. A simple clinical classification is offered as a guide to operative management and a reliable index of prognosis. Patients with clinically apparent, "manifest cancer" have serious, life-threatening disease; many such patients die of their disease. Patients with "neck lumps not yet diagnosed" usually have papillary carcinoma; their prognosis is excellent. Patients whose thyroid tumours fall into the category of "malignant nodule" or "pathologist''s cancer" are particularly fortunate: in this series no such patient has died. The importance of age in relation to thyroid cancer is also confirmed: non of the patients first treated before the age of 40 years has died of cancer. For young patients with favourable disease the author recommends conservative surgical treatment, which avoids cosmetic deformity or functional disability, to be followed by administration of levothyroxine to suppress production of thyroid=stimulating hormone. For patients with "unfavourable" thyroid cancer valuable palliation can often be achieved by a combination of surgery and irradiation. Survival rates for the total series are 76% at 5 years and 60% at 10 years.     

The role of liquid-based cytology in the investigation of thyroid lesions

Objective:  This study investigates the role of liquid-based cytology by ThinPrep^® technique in the detection of thyroid lesions.
Methods:  In all, 252 specimens from 157 patients for pre-operative evaluation of thyroid nodules, prepared by the ThinPrep^®, were examined. In all cases thyroidectomy followed the initial cytological evaluation. All cytological diagnoses were correlated to the histological ones.
Results:  According to our findings, a sensitivity of 87.80%, a specificity of 99.50%, a positive predictive value of 97.30%, a negative predictive value of 97.56% and an overall accuracy of 97.52% were observed in fine needle aspiration cytology in correlation to the histological diagnosis after thyroidectomy.
Conclusions:  ThinPrep^® technique is a valid method for the pre-operative cytological diagnosis of thyroid nodules, offering the possibility of ancillary techniques, such as immunocytochemical and molecular methods and can, therefore, be potentially complementary to histological evaluation for further investigation of follicular lesions.