As chordate body plans evolved, neuronal connections tended to become centralized and cephalized with a knot of neurons organized into a ganglion at the head of the animal. Neuronal function became more specialized and hierarchically organized. This has been much more elaborated in vertebrates than in the somewhat similar path taken by some arthropod lineages. Vertebrate CNS development involves most of the signaling, transduction, transcription, receptor, patterning, and combinatorial expression phenomena that we have seen many times, as well as mechanisms for highly controlled migration of cells through areas already inhabited by other cells.
Early in the evolution of the vertebrate CNS, the brain stem was the only "cerebral ganglion" that could receive and process sensory information, and this is still the way that the nervous systems of some vertebrates are organized. The lancelet, or amphioxus, is an example of a modern "lower" chordate with a notochord and a nerve cord above it, but no brain, no eyes, and, in fact, no head. Over evolutionary time, although the more "advanced" anterior parts of the brain grew larger, much of the synaptic organization of the brain stem was conserved and modified. Some sensory nerves still make synapses (connections) in the brain stem on their way to processing centers in higher, more recently evolved regions of the brain (Matthews 2001).
Why did an organized nervous system that is centralized at one end evolve, and why at the front? One obvious answer is that "front" is basically defined by the direction the animal moves. This centralized end confronts the environment first— if the main sensors responsible for finding food and mates and avoiding predators are close together and localized in an area that first contacts the approaching environment neural connections can be short and the response can be quick and more easily integrated. This is a rather circular explanation, in part because of how we define "front" (and we ignore as exceptions due to phylogenetic inertia those animals, like some crabs, that generally move "backward"). The evolutionary explanations could be countered by saying that the tail end should have the sensors because this is the direction from which the greatest dangers may come or that animals should have eyes in the back and front of their heads (or, like Argus, 100 eyes). Perhaps the brain should be closest to the endocrine organs, to facilitate quick response, or buried deep in the middle of the organism to protect the vital "nerve center," much as military nerve centers are protected in deep underground bunkers. After all, this is how we explain the fact that veins are more superficial than arteries (which, when severed, cause more immediate threat to survival than veins that are severed).
Vertebrate nervous systems are segmented and modular at morphological, histological, cytological, and physiological levels (e.g., Carlson 1999; Redies and Puelles 2001). In some ways, the brain can be thought of as a set of Matryoshka dolls, with major segments composed of smaller units, themselves formed of still smaller ones, in turn made of even smaller ones, and so on, defined in different ways at each step, down to the level of the neuron itself. The brain is physically as well as "virtually" (functionally) segmented, and the distinction is important because under some conditions the physical location of a function can vary or move (and hence, percept, whatever it is experientially, need not be physically localized in the brain). However, not all segments in an adult vertebrate brain correspond to the initial segment structure, and indeed the segments are not always neatly nested; they are generally interdigitated structurally and even functionally.
Segmented Development and Neural Differentiation in Vertebrates
The nervous system is segmented along its anterior-posterior axis from the rostral (face) to the caudal (tail) ends and transversely, that is, dorsoventrally, and also from medial or mesial (inside, central) to lateral or distal (outside, peripheral). In a hierarchical or nested way, segments at an early stage give rise to segmental substages later on. The system initially forms along the dorsal midline, from a layer of cells called the neural plate that overlies an anterior-posterior supporting rod called the notochord (e.g., Carlson 1999; Gilbert 2003; Matthews 2001). The notochord is a source of Shh (Hedgehog class) SF (Gavalas and Krumlauf 2000; Lumsden and Krumlauf 1996; Wurst and Bally-Cuif 2001), which also induces Shh expression in the adjacent overlying neural plate cells. Laterally (on either side of the Shh source) cells express Bmp SF proteins (Bmp4 and Bmp7). In a process called neurulation, this Bmp-expressing flanking tissue grows up and around on either side, closing dorsally to form the top, or roof plate, of a hollow neural tube. The ventral and medial part, the Shh-expressing cells that overlie the notochord, is known as the floor plate. (Recall that Bmp proteins have dorsal effects.)
The Bmp-signaling area is now dorsal, atop the closed tube, and diffuses down both sides, inducing various transcription factors (TFs), including Pax3 and 7 and Msxl and 2, whose expression defines the dorsolateral alar plate. Shh diffuses upward on either side from the floor plate, inducing genes including Pax6 and Nkx TFs to define the ventrolateral basal plate. These expression patterns extend to the spinal cord caudally and are important in establishing regional identity in the forebrain.
The Bmp signal diffusing from lateral ectoderm also induces expression of TFs, including the zinc-finger gene Slug, in cells at the crest of the juncture that formed the roof plate. These cells take on a special role generally considered to be a defining characteristic of vertebrates—perhaps even qualifying as a fourth primary germ layer (Hall 2000)—by becoming the migrating cells of the neural crest (NC), described in Chapter 8. NC cells are involved in peripheral nervous system and cranial neural crest (CNC) in craniofacial bone, tooth, and other tissues.
The extent to which CNC cells are regionally prepatterned before migration away from their source at the neural tube is unclear. CNC cells have plasticity such that to some extent their role is determined by response to signals they meet, possibly including from endoderm, on their migratory way (e.g.,Trainor and Krumlauf 2000). In Chapter 8, we described their interaction with overlying epithelial cells in the process of epithelial-mesenchymal interaction that generates various structures. There is evidence that the overlying tissue has already been prepatterned to produce signaling molecules that induce a response from in-migrating CNC cells, and postcranial NC cells cannot be induced to form head structures (Graveson et al. 1997).
The spinal cord predominates in the control of functions in lower vertebrates, with the brain gaining dominance with the evolution of increasing size of the fore-brain in later vertebrates. Figure 15-3 shows the relative sizes of the major sections of various vertebrate brains. This evolutionary differentiation with its complex behavioral and sensory consequences can thus be viewed as having come about, in part at least, through relatively simple allometric modifications of existing structures that were easy to achieve. Some of the evolutionarily "early" functions remain largely controlled by their original parts of the CNS.
The spinal cord is a collection of nerve fibers and nerve cells in vertebrates that extends from the medulla oblongata at the base of the brain through the spinal column. The number of nerves comprising the spinal cord differs somewhat among vertebrate species, but there is remarkable stability in their position and function. In primates, 31 pairs of nerves, both afferent (incoming sensory) and efferent (outgoing motor), travel along the length of the cord, to emerge at various points between the vertebrae to relay information to and from the brain and the rest of the body. Twelve nerve pairs, the cranial nerves, extend directly from the ventral surface of the brain itself to affect functions in the head and face, as well as some functions in the trunk (e.g., diaphragm). Most of these are both sensory and motor, although the cranial nerves involved in olfaction, vision, and hearing are exclusively sensory.
The brain itself develops as a complex convoluted layer of cells called the cortex that surrounds an inner fluid space (the core of the original neural tube) known as the ventricle. Longitudinally, the brain forms three main regions: the hindbrain (rhombencephalon), the midbrain (mesencephalon), and the forebrain (prosencephalon). The hindbrain functionally divides into the metencephalon, which includes the cerebellum, and the pons and the myelencephalon, which includes the medulla oblongata. A constriction called an isthmus separates the midbrain and hindbrain.
Neurons from the medulla oblongata help to control functions such as breathing, swallowing, cardiovascular function, digestion, and some body movement. The pons, at the junction between the hindbrain and the midbrain, is also involved in regulating breathing. The cerebellum receives sensory information from many parts of the body as well as signals from motor control areas of the forebrain, which it helps to coordinate into motor commands. In popular vernacular, we do not have to "think" about these functions for them to work. They work during sleep and even during coma, and hence do not require consciousness. The rest of the brain is aware a.
°ptic lobe cerebellum
°ptic lobe cerebellum
optic lobe optic lobe
of these functions; for example, they can change circumstantially and can even be influenced by thought, as the racing heart rate triggered by fear.
The hindbrain and midbrain constitute the brain stem. The midbrain contributes to the control of movement and receives sensory information that it passes along to higher areas for interpretation and response. Its major subdivisions are the inferior and the superior colliculus, the first a relay and processing center for auditory signals and the second for visual signals. The reticular formation comprises some of the rest of the midbrain. This section controls the organism's state of arousal and plays a role in various sensory and motor systems.
Figure 15-4 shows the expression boundaries in the hindbrain-midbrain region of many genes that have been examined. Keep in mind the mixed and incomplete dartboard nature of such expression or pathway catalogs. Regional differentiation establishes the isthmus, which then becomes a boundary relative to expression of signaling factors Fgf8 posteriorly and Wnt1 anteriorly. The isthmus is a similarly sharp expression boundary of two TFs: Otx2 anteriorly and Gbx2 posteriorly. Not all genes important in patterning in this area are so restricted, however; En1 and En2 are expressed on either side of the isthmus.
The hindbrain develops into a series of segments called rhombomeres that are reflected in expression boundaries. For example, Krox20 expression differentiates odd from even rhombomeres, and combinatorial expression patterns of genes from the four Hox clusters along with Krox20, Follistatin, Kreisler, and others identify each rhombomere (Voiculescu et al. 2001). This is the anterior-most part of the famous AP combinatorial patterning effect of the Hox clusters presented in Chapter 9 and elsewhere. Consistent with this, experiments that individually inactivate these genes have homeotic (segment-shifting) effects to varying degrees. Functional studies have also shown that these various segment-defining genes interact. Signaling by Fgf8 and diffusible retinoic acid (a morphogen related to vitamin A, not a gene product) and its receptors and binding proteins (which are gene products), affect Hox expression domains and hence rhombomere identity (e.g., Trainor and Krumlauf 2000). Rhombomere-specific gene expression patterns make it possible to trace the migration of NC cells from specific rhombomeres into structures like the pharyngeal (gill) arches (Gavalas and Krumlauf 2000).
A series of genes and their receptors (Eph and Ephrin in Figure 15-4) affect cellular differentiation in the region, and most of the genes shown, which are important to hindbrain specification, are also involved in other developmental processes; for example, Follistatin is a secreted molecule involved later in life in controlling reproductive hormone levels.
The isthmus is frequently referred to as an "organizer" because, like Spemann's, the apical ectodermal ridge (AER) in the developing limb, enamel knots in teeth, the focal Dll spot on butterfly wings, and numerous others, it is a source of signaling molecules that help induce subsequent development in receiving cells around it. Thus, Fgf8 signal emanating from the isthmus inhibits expression of HoxA2 that helps define the anterior hindbrain subregion and in turn is part of the specification of NC cells migrating from the hindbrain to affect skeletal development in the jaws. Hox genes are expressed in the mandibular arch of embryonic agnaths, suggesting that the loss of this expression enabled the anterior pharyngeal arch to evolve into a jaw (Cohn 2002).
However, this is a useful place to restate the caveat that "organizer," like "master" and "selector," is a concept with complex meanings in the culture of the scientists prosencephalon
mesencephalon rhombencephalon prosencephalon
Bmp, Wnt mesencephalon rhombencephalon
eye alar basal plate plate eye alar basal plate plate mesencephalon ri r2 r3 r4 r5 r6 r7 rS
Figure 15-4. Longitudinal segmentation and associated gene expression in the early vertebrate brain. Schematic and selected (and many genes are not yet known). "Is" denotes the isthmus; p1-p6 prosomeres, and r1-411 the rhombomeres. Genes shown are Hox cluster genes, other TFs (Drox20, Kreisler, En1&2, Gbx2, Otx2, Pax, Meis2); SFs and receptors (Eph, Ephrin, Fgf, Wnt); factors related to retinoic acid and its receptors and binding proteins (rara, rarb, Crabp1). Composite based on (Gavalas and Krumlauf 2000; Lumsden and Krumlauf 1996; Marin and Rubenstein 2002; Pasini and Wilkinson 2002; Simeone 2000; Wilson and Rubenstein 2000; Wurst and Bally-Cuif 2001).
coining such usages in genetics. As such, the term can be misperceived to suggest a discrete, externally imposed purposive entity, rather than a basically quantitative region vs. qualitative entity, which itself arises from prior signaling interactions (Wilson and Rubenstein 2000). It is called an organizer because it is a regional source of signal that affects the development—sometimes but not always with sharp boundaries—of subsequent structures. In fact, things are not so simple and the defining genes are not the only important factors in phenomena affected by their production in the isthmus (e.g., Chambers and McGonnell 2002), nor is the isthmus the only place they are important even, even in neural development.
The forebrain, or prosencephalon, is generally thought of (anthropocentrically) as the place where the really important biological traits reside: where vertebrates interpret, integrate, and respond to sensory and somatic input and motor commands (e.g., Matthews 2001).The relative size of the forebrain varies greatly in vertebrates, from being among the smallest sections of the brain of fish and reptiles, to constituting most of the brain in primates. Many of the functions carried out in this part of more complex brains, such as visual processing, occur in the midbrain of animals with small forebrains, although some of the "higher" functions are missing from the latter. (Does this mean they "perceive" vision differently?) It is perhaps worth considering that, from the point of view of members of species without forebrains—species that are doing perfectly well in the world—the forebrain might seem a grotesquely exaggerated tissue that requires a lot of extra DNA, metabolic energy, and maintenance, and thus a lot of food. This belies any notion that evolution is an energetically parsimonious phenomenon.
Each part of the brain is further subdivided into sections with their own specialized functions. Our understanding of the degree to which specific functions, other than the major obvious ones like vision and olfaction, are precise and replicable is still incomplete but scans of brain activity under various conditions and in experimental animals whose brains have been modified, or affected by certain diseases, show that functions can be remarkably tightly located. That is, brain activity changes only in a very localized region of the forebrain during the experimental or test experience.
The forebrain develops from an outpocketing of anterior neural tissues (first to form the optic vesicle) and is affected by signaling from several major regions (for a detailed discussion of these complex processes see Marin and Rubenstein 2002); these are generally indicated in Figure 15-4. Early dorsal signals involve Bmp and Wnt genes. A second signaling area of importance in forebrain development is the anterior neural plate (ANP).This most rostral area is another source of Fgf8 signal in the developing brain and is also referred to as a forebrain organizer. Ventrally, forebrain development is affected by Shh to which we have already referred.
The outgrowth forms a hollow structure on each side, with a dorsal groove or sulcus between them that separates the future left and right cerebral hemispheres. Also forming are areas of thickening, including the ventral septum and the medial and lateral ganglionic eminences (MGE and LGE), as indicated by the transverse sections shown in Figure 15-5. Ventral to these areas are the anterior entopeduncu-lar area and associated anterior preoptic area, where major tracts of neural fibers go into or come out of the telencephalon. Darker shading indicates the ventricular zone
(VZ) in which neural stem cells produce differentiated glial and neuronal cells that move into the adjoining subventricular zones (lighter shading). The dorsal region (dorsal and medial pallium in the figure) becomes the cortex.
The prosencephalon can be viewed as being divided into six segments called pro-someres, by analogy to rhombomeres, though the most anterior three of these are less clearly defined. Prosomeres are characterized by differential gene expression patterns (e.g., Marin and Rubenstein 2002).The diencephalon and the telencephalon are the major subsequent divisions of the forebrain. These, however, are further divided—the diencephalon into the thalamus and the hypothalamus and the telen-
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