This chapter describes the role played by transcriptional factors in osteoblast differentiation and function. Till date, only one transcription factor has been identified that is specifically expressed in cells of the osteoblast lineage, Cbfa1 (core binding factor 1). Cbfa1 expression in osteoblasts is maintained after birth, and Cbfa1 controls the expression of Osteocalcin, for instance, a gene only expressed in fully differentiated osteoblasts. Cbfa1, like all transcription factors belonging to the Runt family, contains a DNA-binding region of 128 amino acids, called the runt domain, followed C-terminally by a proline-serine-threonine-rich region, called the PST domain. The PST domain contributes to the transactivation function of Cbfa1 and contains a short sequence at the C terminus that mediates transcriptional repression through interactions with TLE2. Cbfa1 has two unique domains located at the N terminus that are also involved in activating transcription. One of them, the so-called QA domain, which is rich in glutamine and alanine, prevents heterodimerization of Cbfa1 with Cbfβ, a known partner of other Runt family transcription factors. As haploinsufficiency at the Cbfa1 locus leads to severe skeletal dysplasia, it is conceivable that a moderate increase in the level of Cbfa1 may lead to increased bone formation by activating either, osteoblast differentiation or function. Several lines of evidence suggest that members of the AP-1 family are involved in the regulation of osteoblast differentiation. AP-l binding sites have been found in the promoter regions of several genes expressed in osteoblasts, including alkaline phosphatase and Osteocalcin. Various extracellular signaling molecules, such as TGFβ and PTH, have also been shown to induce the expression of AP-1 components in osteoblastic cells.
HISTORICAL BACKGROUND One of the most striking characteristics about the craniofacial bones is that, contrary to the rest of the vertebrate skeleton, they are not entirely of mesodermal origin. Embryological studies, which started at the end of the 19th century with the observations of Kastschenko (1888, for selacians) and Goronovitch (1892, 1893, for teleosts and birds), have established that mesenchymal cells can arise, not only from the mesodermal, but also from the ectodermal germ layer. During this period, Julia Platt was the first to propose in 1893 that ectoderm contributed not only to the mesenchyme, but also to the cartilage of the visceral arches and to the dentine of the teeth in the mud puppy, Necturus . This derivation of mesenchyme, bones and cartilages from the ectoderm, was shown to occur via a transient structure, the Neural Crest (NC), which was first described in the chick embryo by the German Histologist Wilhem His in 1868. These observations contradicted the germ layer theory first put forward by Christian Heinrich Pander (1817), who described the formation of three layers of cells from the chick blastoderm. Later, Karl von Baer (1828) extended Pander’s findings to all vertebrate embryos. In 1849, Thomas Huxley generalized the presence of germ layers to invertebrates and the terms ectoderm, mesoderm , and endoderm were first used to designate the vertebrate germ layers by Ernst Haeckel in 1874, in the context of the Gastrea concept. The observation that formation of germ layers precedes organ morphogenesis and cellular differentiation was followed by...
Bone is a form of highly specialized mineralized connective tissue that provides strength to the skeletal system of higher vertebrates, while still retaining a certain degree of elasticity. The bone matrix is produced by osteoblasts, a cell-type that develops locally from mesenchymal precursors, and is resorbed by the osteoclast, a cell-type of hematopoietic origin. A few elements, such as the flat bones of the skull and part of the clavicle, are formed by the process of intramembranous ossification, whereby osteoblasts differentiate directly from cells within mesenchymal condensations. In contrast, the majority of skeletal elements are formed by endochondral ossification involving the remodeling of initial cartilaginous templates into bony tissue. The latter process requires controlled maturation of chondrocytes from proliferating and prehypertrophic to hypertrophic chondrocytes, as well as signaling from the prehypertrophic cells to the surrounding cells in the perichondrium, resulting in a regional induction of osteoblast differentiation. Osteoblasts start to differentiate in the periosteum, a region flanking prehypertrophic and hypertrophic chondrocytes. The typical appearance of one end of a juvenile long bone still containing a cartilaginous growth plate is shown in Figure 1. Recent lineage studies suggest that osteoblasts and chondrocytes share a common precursor in the limb. Thus, especially in the limb, the activation and/or inhibition of distinct signaling pathways is necessary in order to coordinate the differentiation of neighboring cells into distinct cell lineages and to synchronize their maturation. This chapter focuses on genetic and molecular studies elucidating the role of different locally produced growth factors during embryonic...
Bone formation occurs through two distinct processes. Most skeletal, elements form by endochondral ossification, which involves a cartilage intermediate. The other skeletal elements, which mainly include craniofacial bones, are formed by a process of intramembranous ossification, whereby bones form directly from mesenchymal condensations without involvement of a cartilage intermediate. In addition to forming the templates for the development of endochondral bones, cartilage is also present as a permanent connective tissue at the ends of bones (articular cartilages) and in ear, nose, and throat tissues. Chondrogenesis is a multistep process that begins with the commitment of mesenchymal cells to a chondrogenic cell lineage (Fig. 1). These cells then aggregate into condensations that prefigure the future shape of endochondral bones. Cells in these mesenchymal condensations overtly differentiate into chondrocytes and produce a characteristic cartilage extracellular matrix (ECM). These cells then undergo several more changes. The first is a unidirectional proliferation that results in parallel columns of dividing cells that fuel the longitudinal growth of bones. In contrast to the overtly differentiated chondrocytes, which are round cells, the proliferating chondrocytes in these parallel columns have a flat morphology. These cells then exit the cell cycle, gradually change their genetic program, and become prehypertrophic and then hypertrophic chondrocytes. The most mature hypertrophic chondrocytes, which acquire the ability to mineralize their ECM, later die by apoptosis. In endochondral skeletal elements, first a thin layer of mesenchymal cells on the periphery of the condensations forms the perichondrium, which subsequently develops into the periosteum. Cells in the...
During the past 25 years, the use of genetic approaches has contributed substantially to the understanding of skeletal development and growth. Identification of mutations responsible for a large number of human osteochondrodysplasias and dysostoses (Mundlos and Olsen 1997a,b) has provided insights into the roles not only of individual genes, but also of entire developmental pathways. The correlation of clinical phenotypes with molecular alterations has allowed analyses of structure-function relationships. Coupled with studies of the phenotypic consequences of gene mutations in inbred mouse strains, and more recently also in zebrafish, such analyses have resulted in deep insights into the genetic mechanisms that underlie skeletal assembly, growth, maintenance, and functions. SKELETAL DEVELOPMENT AND GENETIC DISORDERS The vertebrate skeleton is the product of mesenchymal cells (osteochondroprogenitors of cartilage-forming chondrocytes and bone-forming osteoblasts) derived from cranial neural crest, paraxial mesoderm, and lateral plate mesoderm (Olsen et al. 2000). Bone marrow-derived myeloid cells are the progenitors for bone- and cartilage-resorbing cells, called osteoclasts. Neural crest cells give rise to the branchial arch derivatives of the craniofacial skeleton, paraxial mesoderm contributes to both the craniofacial and the axial skeleton, and the lateral plate mesoderm supplies progenitor cells for the limb skeleton (Fig. 1). Progenitor cells from these sources migrate into the regions in which future bones are formed, condense into elements of high cellular density, and differentiate into either osteoblasts or chondrocytes. Osteoblastic differentiation, followed by synthesis of bone extracellular matrix, occurs in regions of membranous ossification, such as the calvarium of the skull, the maxilla,...
Bone remodeling refers to the renewal process whereby small packets of old trabecular and cortical bone, dispersed throughout the skeleton and separated from others geographically as well as chronologically, are replaced by new bone throughout adult life. A major feature of bone remodeling is that it does not occur uniformly throughout the skeleton, but takes place asynchronously in focal or discrete sites known as basic multicellular units (BMUs) of bone turnover (Frost 1964; Parfitt 1996). The BMU describes the cells within a packet of bone that is resorbed and then fully rebuilt. The resorption activity in a BMU in human bone takes approximately 3 weeks and the formation response takes 3–4 months. The process is such that remodeling replaces about 5%–10% of the skeleton each year, with the entire adult human skeleton replaced in 10 years. Understanding the tightly-controlled processes of bone resorption and formation that take place in individual BMUs throughout the skeleton requires appreciation of the many pathways that control cells of the osteoblast and osteoclast lineage and how they communicate among themselves. SEQUENCE OF CELLULAR EVENTS IN BONE REMODELING: OSTEOCYTE INVOLVEMENT Cancellous bone remodeling starts on the bone surface, initiated by any of several possible stimuli. Among these are pressure changes sensed by osteocytes, resulting in signals delivered to surface cells, and damage in the form of microcracks in bone that lead to osteocyte stimulation, or even apoptosis, and the release from other nearby bone cells of signals, some of which are likely to be...
The vertebrate skeleton is composed of approximately 200 bones, ranging in shape and size from the delicate bones of the mammalian inner ear to the robust femur. Each individual bone forms in a precise location and orientation with respect to its neighbors and in relation to force generating and transmitting tissues—the muscles, tendons, and ligaments. The appropriate structure of the bones is essential for function of the skeleton to support and move the body, and depends on an array of molecular cues that pattern their formation early in development. Our knowledge of developmental mechanism patterning all tissues and organs of the body, including the skeleton, is largely derived from experiments using two model systems—chick and mouse embryos. While aspects of patterning the craniofacial and axial skeletal elements have been elucidated, development of the bones of the limbs is particularly well understood. The limbs are easily accessible for embryological manipulation and are expendable for the survival of prenatal animals, allowing for analysis of late developmental phenotypes after genetic or surgical perturbation. The developing limb bud has therefore become an important model for the investigation of cellular and molecular mechanisms that pattern the tissues that give rise to bones. The tetrapod limb is of additional interest from an evolutionary perspective because it is a conserved but malleable structure whose adaptive variations in form increase an animal’s fitness in different ecological niches—by promoting mobility, aiding in the acquisition of food, fighting against or escaping from predators, and assisting in reproduction...
One of the most striking features of the human spine is its periodic organization. This so-called “segmental” arrangement of the vertebrae along the anteroposterior body axis is established during embryonic development. Structures called somites, which contain the precursors of the vertebrae, form in a rhythmic fashion at the posterior end of the embryo during the process of somitogenesis. Somites are sequentially added to the growing axis, thus establishing the characteristic periodic pattern of the future vertebral column. The primary segmentation of the vertebrate embryo displayed by somitic organization also underlies much of the segmental organization of the body, including muscles, nerves, and blood vessels. In amniotes, somites are the major component of the paraxial mesoderm that form bilaterally along the nerve cord as a result of primitive streak and tail bud regression during body axis formation. Somites bud off from the anterior presomitic mesoderm (PSM) as epithelial spheres surrounding a core of mesenchymal cells called the somitocoele. The dorsal portion of the somite remains epithelial and forms the dermomyotome, which differentiates into muscle and dermis while its ventral moiety undergoes an epithelio-mesenchymal transition, leading to the formation of the sclerotome. The sclerotome gives rise to the skeletal elements of the vertebral column: the vertebrae, ribs, intervertebral disks, and tendons. Most of our understanding of amniote somitogenesis at the morphogenetic and molecular levels results from studies involving the chicken ( Gallus gallus ) and the mouse ( Mus musculus ). In this chapter, we essentially focus on the patterning and development of the spine in...
The extracellular matrix (ECM) is a highly heterogeneous amalgam of multidomain molecules that are intimately involved in the development, growth, function, and homeostasis of every organ system, including the skeleton. Similar to other connective tissues, bone and cartilage matrices consist of collagens, proteoglycans (PGs), and noncollagenous (NC) proteins, in addition to including enzymes involved in matrix assembly and degradation. That the vast majority of these molecules are also found in other tissues indicates that relative differences in ECM composition specify form and function at discrete anatomical locations of the developing and adult skeleton. This chapter provides an introduction to ECM composition and organization in the skeleton, and a brief review of the contribution of selected matrix molecules to bone formation and remodeling that is mostly based on genetic evidence from loss-of-function studies in mice. Similar topics are also covered in other chapters of this book, and a number of excellent reviews are available that describe various aspects of ECM biology in greater detail. ECM COMPOSITION AND ORGANIZATION Collagens Collagens are the most abundant and diverse components of the connective tissue (Mecham 1998; Birk and Bruckner 2005). All collagens possess at least one triple helical (or collagenous [COL]) domain and NC domains of variable length and composition. Most collagens give rise to morphologically diverse suprastructures that are also referred to as molecular composites because they include additional collagens and NC proteins (Birk and Bruckner 2005). For example, tissue-specific organization of collagen I or II networks is largely regulated by copolymerization with...
The mechanisms by which mineralized tissues such as bone acquire and regulate their mineral component are complex. The process of mineralization can be divided into the establishment of a primed, mineralizable matrix in which de novo mineral nucleation can occur, followed by the growth, expansion, and maturation of crystals. Perturbations in any of these events can result in bone disease and fragility. Elucidating the cellular and molecular mechanisms has been difficult because biomineralization is a combination of a physico-chemical process and a biological one. For example, phosphate participates directly in the formation of the hydroxyapatite crystals but recent studies have shown that phosphate can also directly regulate gene expression. This chapter summarizes current opinion within the field on key issues related to mineralization, such as whether mineralization is an active (cell-mediated) or a passive (physico-chemical) process and the role of cell-derived organelles/vesicles in mineralization. The molecular mediators and regulators of mineralization are reviewed and the question of whether there are unique mechanisms of mineralization in different types of bone tissue is addressed. Even though bone mineral density is currently the standard for predicting bone fragility, it is important to not only understand the inorganic component of bone, but also the organic component, as individuals with similar bone densities can have different susceptibility to fracture. These less clear properties of the skeleton that contribute to bone strength remain the focus of much investigation. THE CELLS RESPONSIBLE FOR BONE FORMATION AND MINERALIZATION Cells in the osteoblast/osteocyte lineage are responsible for bone formation...
I. INTRODUCTION The purpose of this chapter is to describe the processing of pre-tRNAs in yeast, integrating information on processing in the nucleus and mitochondria. Precursor tRNAs produced from nuclear genes and mitochondrial genes have the same general requirements: Various activities are needed to remove 5´leaders and 3´trailers, to add the CCA end, and to catalyze numerous base modifications (Fig. 1). In addition, a subset of nuclear pre-tRNAs have introns that must be removed, although no such activities are required for the biogenesis of any yeast mitochondria1 tRNA. Some yeast nuclear tRNA genes are transcribed together in dimeric pairs (Schmidt et al. 1980), and mitochondria1 tRNAs are transcribed with other tRNAs (Palleschi et al. 1984b; Martin et al. 1985b; Bardonne et al. 1987; Francisci et al. 1987), with ribosomal RNAs (Osinga et al. 1984; Palleschi et al. 1984a), with mRNAs (Miller et al. 1983; Zassenhaus et al. 1984), or with the RNasc P RNA (Shu and Martin 1991). Although these polycistronic transcripts are processed by a variety of activities, only those directly involved in tRNA recognition and processing are considered here. We have not attempted to review tRNA gene organization or transcription, as these topics have been covered elsewhere. The reader is referred to Guthrie and Abelson (1982) for a review of yeast nuclear tRNA genes, to Thuriaux and Sentenac (this volume) for a review of nuclear tRNA gene transcription, and to Tzagoloff and Myers (1986) for a review of mitochondria1 tRNA genes. In general, we have...
Most living vertebrates are characterized by possession of bones and cartilage as major components of the skeletal system, and the origin and evolution of these tissues remain intriguing questions. Classically, Geoffroy Saint-Hilaire (1818) tried to compare arthropods and vertebrates by two types of “inversions.” One is the dorsoventral inversion that brings the ventral nervous system of arthropods to the dorsal side, as seen in vertebrates. The other is the inside-out inversion to transform the arthropod exoskeleton into the vertebrate-type endoskeleton. However, it is misleading to regard the endoskeleton as the major skeleton in vertebrates. Compared with the exoskeleton in arthropods, vertebrates also have exoskeletal elements. Thus, the vertebrate exoskeleton has been compared directly with that of arthropods, as suggested by Patten (1912), Gaskell (1908), and others. However, those ideas have now been refuted by new evidence of phylogenetic relationships among animal phyla, by improved knowledge of skeletal histology and cytology, and by molecular developmental evidence for skeletogenesis. In the modern evolutionary scenario, which is largely based on phylogenetic trees constructed on molecular sequence data, it is generally accepted that vertebrates belong to the deuterostomes together with echinoderms, hemichordates, urochordates, and cephalochordates (amphioxus). This comprises a sister group to the protostomes, consisting of lophotrochozoans and ecdysozoans (Aguinaldo et al. 1997). It is along this phylogenetic tree that the origins of the vertebrate skeleton should be sought, by integrating the fossil evidence (Halstead 1974; Donoghue and Sansom 2002; Hall 2005). Comparative analyses of skeletal development in various living organisms will help guide...
Osteoclast differentiation is an important biological process that determines the level of bone resorption in vivo. Numerous cytokines and growth factors are involved in the regulation of this process by directly acting on osteoclast precursor cells or through their effect on osteoclastogenesis-supporting mesenchymal cells, such as osteoblasts. Receptor activator of NF-κB ligand (RANKL) is an essential cytokine that promotes osteoclastogenesis and, in most cases, the effects of other factors can be explained in the context of cross talk with RANKL signaling. This chapter describes recent advances in the understanding of the intracellular signaling mechanism of RANKL and its interaction with other signaling events during osteoclastogenesis, which may provide a molecular basis for therapeutic intervention in pathological bone resorption. THE ESSENTIAL ROLE OF THE RANKL-RANK SYSTEM IN OSTEOCLASTOGENESIS Osteoclast differentiation is a tightly regulated process because the balance between osteoclasts and osteoblasts is critical for bone homeostasis. Osteoclasts differentiate from hematopoietic cells of monocyte/macrophage lineage, but osteoclastogenesis-supporting cells of mesenchymal origin are required for the differentiation commitment. Thus, osteoclasts have traditionally been formed in a coculture of hematopoietic cells derived from bone marrow and calvarial osteoblasts, which were thought to express an unknown osteoclast differentiation factor. Before this factor was identified, information about the molecules involved in osteoclast differentiation had been obtained from the analysis of osteopetrotic mice (Fig. 1) (Asagiri and Takayanagi 2006). RANKL, a type II membrane protein of the TNF superfamily, was identified as the long sought-after osteoclast differentiation factor expressed by osteoblasts, but interestingly, the same molecule...
Chondrogenesis, whether during the formation of cartilage models during endochondral bone formation, longitudinal and apositional growth, maintenance of the articular surfaces, or during repair and healing, is a carefully orchestrated multistep process. As such, regulation of this process requires the interplay of a large number of factors, including inductive cues from surrounding tissues, intercellular signals emanating from within the cartilage itself, and intrinsic factors within the chondrocytes. Indeed, intrinsic and extrinsic regulation are intimately related to one another. In response to specific sets of growth factors, cells at various stages of chondrogenic differentiation activate expression of unique sets of transcription factors committing them to, and defining, particular cell states. In turn, a consequence of the expression of these transcription factors is the regulated production of stage-specific secreted proteins that feedback on other chondrogenic cells. Of equal importance, the transcriptional state of cells in the chondrogenic pathway determines their ability to respond to specific factors and the nature of their response. These intrinsic and extrinsic factors are thus components of a complex integrated network, a fact that must be borne in mind while considering any one aspect of chondrogenic regulation. Nonetheless, given the incomplete nature of our current understanding of chondrogenesis, and the complexity of the problem, it is perhaps easiest to organize a discussion of chondrogenesis by considering inductive factors and intrinsic regulation individually. This review focuses on the secreted proteins and signal transduction systems that regulate various aspects of chondrogenesis, while the transcription factors upstream and downstream of these...
Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Adult neurogenesis decreases with age but remains present, albeit at a very low level, even in the oldest individuals. Activity, be it physical or cognitive, increases adult neurogenesis and thereby seems to counteract age effects. It is, thus, proposed that activity-dependent regulation of adult neurogenesis might contribute to some sort of "neural reserve," the brain's ability to compensate functional loss associated with aging or neurodegeneration. Activity can have nonspecific and specific effects on adult neurogenesis. Mechanistically, nonspecific stimuli that largely affect precursor cell stages might be related by the local microenvironment, whereas more specific, survival-promoting effects take place at later stages of neuronal development and require the synaptic integration of the new cell and its particular synaptic plasticity.
Aging is a complex process involving the additive effects of many genetic pathways (Kirkwood and Austad 2000). To embrace the complexity of aging, an attractive approach is to use DNA microarrays to scan the entire genome for genes that change expression as a function of age or under conditions when longevity is extended. The list of age-regulated genes provides clues about genetic pathways and mechanisms that underlie the aging process. In addition to single-gene analysis, the combined transcriptional profile of aging can act as a molecular phenotype of old age. During the last 20 years, there has been a great deal of effort to search for biomarkers of aging, and recent studies have shown that expression profiles of aging derived from DNA microarray experiments may provide this long-desired goal. A gene expression signature for aging is a quantitative phenotype that gives a high-resolution view of the aging process, much like using transcriptional profiles of cancer to inform about their severity or malignancy. Previously, one could recognize old versus young individuals in a photograph, or old versus young tissue on a microscope slide. Now it is possible to recognize old versus young genetic networks by analyzing expression levels of the entire set of age-regulated genes (Fig. 1). Unlike photographs or micrographs, expression data from DNA microarrays are quantitative, and thus it is possible to compare age-related transcriptional profiles between different tissues, between different conditions that affect longevity, and even between diverse species. Such comparisons are not possible by browsing images of...
In the adult mammalian brain, new neurons are added to the olfactory bulb (OB) throughout life. In rodents, the adult germinal region for OB neurogenesis is the subventricular zone (SVZ), a layer of cells found along the walls of the brain lateral ventricles (for review, see Alvarez-Buylla and Garcia-Verdugo 2002). Neuroblasts born in the SVZ migrate a relatively long distance into the OB where they then disperse radially and differentiate into interneurons. Most of these new OB neurons integrate into functional circuits (Belluzzi et al. 2003; Carleton et al. 2003), and about half survive long-term (Petreanu and Alvarez-Buylla 2002). SVZ cell proliferation is lifelong (Kuhn et al. 1996; Goldman et al. 1997; Molofsky et al. 2006), with thousands of new neurons generated daily for the mouse OB (Lois and Alvarez-Buylla 1994). The adult SVZ is also the birthplace of oligodendrocytes in both normal and diseased brain (Nait-Oumesmar et al. 1999; Picard-Riera et al. 2002; Menn et al. 2006; Parent et al. 2006). This profound level of continuous neurogenesis and concomitant oligodendrogliogenesis argues for the existence of a self-renewing multipotent precursor cell—or, neural stem cell (NSC)—within the SVZ. The SVZ-OB system is an attractive model in which to study neurogenesis and neuronal replacement as it includes the basic processes of NSC maintenance, progenitor cell-fate specification, migration, differentiation, and survival/death of newly born neurons. The enduring quality and stable cytoarchitecture of adult SVZ-OB neurogenesis may make these complex biological processes experimentally more tractable in comparison to studies of embryonic brain...
As outlined in the previous chapter, the biochemical characterization of human transforming growth factor-β (TGF-β), now known as TGF-β1, and the determination of its sequence through cDNA cloning provided the basis for identification of TGF-β as structurally distinct from TGF-α. The most striking characteristic that set it apart from TGF-α at that time was that TGF-β was a 25-kD disulfide-linked dimer that was reduced to a 12.5-kD band on gel following treatment with β-mercaptoethanol (Roberts et al. 1983). Following its cDNA cloning (Derynck et al. 1985), it became apparent that TGF-β did not at all resemble TGF-α to which it had been functionally compared thus far and that its polypeptide sequence was unrelated to anything known before. The predicted polypeptide sequence also clearly showed that the mature TGF-β monomer corresponded to only the carboxy-terminal third of a much larger precursor, thus requiring proteolytic cleavage (see Fig. 3 of Chapter 1). Subsequent cDNA cloning demonstrated that the polypeptide chains that define the heteromeric disulfide-linked inhibin are structurally related to TGF-β (Mason et al. 1985; Vale et al. 1986). These polypeptides are, similarly to TGF-β, encoded as carboxy-terminal polypeptides of larger precursors, and only the carboxy-terminal mature polypeptides show structural similarity with TGF-β. Thus was born the realization that there may be a family of secreted disulfide-linked dimeric polypeptides encoded as carboxy-terminal segments of larger secreted polypeptides. This realization was further borne out by the cDNA cloning of bone morphogenetic protein-2A (BMP-2A) and BMP-2B, now known as BMP-2 and BMP-4, respectively (Wozney...
Most organisms rely on an olfactory system to detect and analyze chemical cues from the external world in the context of essential behavior. From worms to vertebrates, chemicals are detected by odorant receptors expressed by olfactory sensory neurons, which send an axon to the primary processing center—the olfactory bulb, in vertebrates. Within this relay, sensory neurons form excitatory synapses with projection neurons and with inhibitory interneurons. Thus, due to complex synaptic interactions in the olfactory bulb circuit, the output of a given projection neuron is determined not only by the sensory input, but also by the activity of local inhibitory interneurons that are concerned by adult neurogenesis throughout life. Recent studies have provided clues about how these new neurons incorporate into preexisting networks, how they survive or die once integrated into proper microcircuits, and how basic network functions are maintained despite the continual renewal of a large percentage of neurons. We know that external influences modulate the process of late neurogenesis at various stages. Thus, this process is probably flexible, allowing brain performance to be optimized for its environment. But optimized how? And why? This chapter describes the adaptation of new interneuron production to experience-induced plasticity. In particular, how the survival of newly generated neurons is highly sensitive not only to the level of sensory inputs, but also to the behavioral context is discussed. Also discussed is how neurogenesis may finely tune the functioning of the neural network, optimizing the processing of sensory information. Adult neurogenesis maintains continual turnover...
