Isabelle Franceschini

Schwann cell-like myelination following transplantation of an olfactory bulb-ensheathing cell line into areas of demyelination in the adult CNS

In this study we have transplanted a clonal olfactory bulb‐ensheathing cell line into focal areas of the rat spinal cord which contain demyelinated axons but neither oligodendrocytes nor astrocytes. The cell line was created by retroviral incorporation of the temperature‐sensitive Tag gene into FACS‐sorted 04+ cells from 7‐day‐old rat pup olfactory bulb. The spinal cord lesions were obtained by injecting small volumes of ethidium bromide into the dorsal white matter of spinal cord previously exposed to 40 Grays of X‐irradiation. Many of the axons were remyelinated by P0+ myelin sheaths 21 days after transplantation. Light and electron microscopy revealed cells engaging and myelinating axons in a manner highly reminiscent of Schwann cells within similar lesions. GFAP+ cells were also present within the lesion. This study provides the first in vivo evidence that olfactory bulb‐ensheathing cells are able to produce peripheral‐type myelin sheaths around axons of the appropriate diameter.

Emerging new sites for adult neurogenesis in the mammalian brain: a comparative study between the hypothalamus and the classical neurogenic zones

In adult mammalian brain, two main germinative regions located in the subventricular zone of the lateral ventricle and in the subgranular cell layer of the hippocampal dentate gyrus have been considerably documented and are still under intense scrutiny. However, new neuron formation has recently been reported in various other brain areas including the hypothalamus. This central structure, responsible for the control of many major neuroendocrine functions such as reproduction, expresses high levels of PSA‐NCAM and nestin, both proteins being involved in structural and morphological plasticity mechanisms. Cell proliferation and new neuron production have been demonstrated in the adult hypothalamus of numerous species, although not hitherto described in non‐human primates and humans. Similarly to the subventricular zone and in the subgranular cell layer, the adult hypothalamic neurogenesis process is subject to dynamic regulation by various physiological and pharmacological signals. Several pieces of evidence support the hypothesis that a stem cell niche‐like architecture exist in the hypothalamus region lining the third ventricle thereby enabling adult neural stem cells to continuously generate neurons in vivo throughout life. Furthermore, recent data indicating that new hypothalamic neurons may become functionally implicated in sensory information processing endorse the assumption that the hypothalamus might be a neurogenic region.

Neuregulin is a mitogen and survival factor for olfactory bulb ensheathing cells and an isoform is produced by astrocytes

The rat olfactory bulb is an exceptional CNS tissue. Unlike other areas of the brain, growing axons are able to enter the olfactory bulb and extend within this CNS environment throughout adult life. It appears that the glial cells of the olfactory system, known as olfactory bulb ensheathing cells (OBECs), may have an important role in this remarkable process of CNS neural regeneration. OBECs are unusual glial cells, possessing properties of both astrocytes and Schwann cells. In this study we show that astrocytes (in the form of astrocyte‐conditioned medium; ACM) produce two critical regulatory functions for OBECs: mitogenic activity and a survival factor. Interestingly, the ACM‐derived activity for OBECs appears to reside in a signalling protein(s) belonging to the neuregulin (NRG) family of growth factors, and specifically appears to coincide with one or more products of the nrg‐1 gene. Our observations provide evidence for the following: recombinant human neu differentiation factors (NDFβ1, ‐2 and ‐3) are mitogenic to OBECs; the activity in ACM can be neutralized by NDF antibodies; these same antibodies detect a 50‐kDa, non‐heparin binding protein in concentrated ACM; astrocytes express detectable nrg‐1 transcripts; and OBECs express functional NRG receptors erbB2 and erbB4.

The intimate relationship of gonadotropin-releasing hormone neurons with the polysialylated neural cell adhesion molecule revisited across development and adult plasticity.

The neurohormone gonadotropin‐releasing hormone (GnRH) is critical for all the aspects of reproductive life in vertebrates. GnRH is secreted by a small number of neurons dispersed within the preoptic‐hypothalamic region. These neurons are derived from the embryonic olfactory pit. They then migrate along olfactory, vomeronasal and terminal nerves to their final destination. Classical approaches to study the regulation of GnRH secretion during the reproductive cycle have focused on the various neuronal inputs on GnRH neurons and their regulation by ovarian steroids. However, it is well known that steroids will change the microenvironment of neuronal networks and can induce plasticity and functional changes. In this review, we will focus on the intimate relationship of developing and adult GnRH neurons with the polysialylated form of neural cell adhesion molecule (PSA‐NCAM), a major molecular actor in the morphogenesis and adult plasticity of the nervous system. We will first recapitulate the spatiotemporal relationship between PSA‐NCAM and migrating GnRH neurons during embryogenesis of various vertebrate species and discuss its importance for GnRH neuron development as shown by various loss of function studies. In the adult, we will review the relationships between PSA‐NCAM and GnRH neurons across various physiological states, and open the discussion to the use of new model systems that can help to unravel the function and mechanism of action of PSA‐NCAM on GnRH neuronal network activity and GnRH release.

Adhesion molecule expression and phenotype of glial cells in the olfactory tract

These data illustrate that OBECs have a highly plastic nature in keeping with their need to respond rapidly to changing environmental cues. This relates to their required function in supporting axonal extension throughout life. Future studies using antibodies to PSA-NCAM and L-NGFr together with FACS sorting to purify the two types of OBEC should give us a clearer understanding of the lineage relationship of the two phenotypes. With purified populations of the astrocyte-like and Schwann cell-like OBEC we should be able to determine if these cells have different functions in vivo, using several approaches namely: i) identifying the growth factors that regulate their growth and differentiation, ii) measuring the ability of the purified cells to remyelinate the experimentally-created CNS lesions and iii) carry out more detailed cellular and molecular comparisons of the two phenotypes.

LA PLASTICITÉ NEURO-GLIALE DES RÉSEAUX NEUROENDOCRINES

Neuro-glial plasticity of neuroendocrine networks is a major mechanism involved in key events of physiological functions such as parturition and lactation (oxytocinergic system) and preovulatory surge (GnRH system). This type of plasticity is classically described as rearrangements between glial cells and neuroendocrine neurones. Neuro-glial plasticity can occur within several hours. Cellular and molecular mechanisms involved are complex and imply an active regulation of neuroendocrine networks activity. In the present study we show that GnRH pulsatile secretion studied in vitro is regulated by gap junction communication between glial cells. Glial cells forming the microenvironment of GnRH neuronal network could represent a new system for integrating environmental cues and for regulating GnRH secretion