Section VIII. The Development of the Nervous System Chapter 52. The Induction and Patterning of the Nervous System Chapter 53. The Generation and Survival of Nerve Cells Chapter 54. The Guidance of Axons to Their Targets Chapter 55. Formation and Regeneration of Synapses Chapter 56. Sensory Experience and the Fine- Tuning of Synaptic Connections Chapter 52: The Induction and Patterning of the Nervous System
z 楊定一 (Ding-I Yang, Ph.D.) z 腦科學研究所 z 辦公室:圖資大樓851室; 分機號碼:7386 z 實驗室:圖資大樓850室; 分機號碼:6150 z E-mail: [email protected] An Overall View z The entire nervous system arises from the ectoderm. z Inductive signals control neural cell differentiation: --neural plate is induced by signals from adjacent mesoderm involving inhibition of bone morphogenetic protein signals. z Neural plate is patterned along its dorsoventral axis by signals from adjacent nonneuronal cells: --ventral neural tube by sonic hedgehog. --dorsal neural tube by bone morphogenetic proteins. --dorsoventral patterning is maintained throughout the rostrocaudal length of the neural tube. An Overall View z The rostrocaudal axis of the neural tube is patterned in several stages: --the hindbrain is organized in segmental units by Hox genes. --the midbrain is patterned by signals from a neural organizing center. --the developing forebrain is subdivided along its rostrocaudal axis. z Regional differentiation of the cerebral cortex depends on afferent input as well as intrinsic programs of cell differentiation. 背部的 嘴側的 尾側的 腹部的
The medial surface of the brain 冠狀的 前後向的 The entire nervous system arises from the ectoderm z Endoderm: the innermost layer gives rise to gut, lungs, and liver. z Mesoderm: the middle layer gives rise to connective tissues, muscle, and the vascular system. z Ectoderm: the outermost layer gives rise to the major tissue of the CNS and PNS. Neural and glial cells derive from neural plate. Ectodermal cells failed to differentiate into neural/glial cells give rise to the epidermis of the skin. Development of Nerve Cell Connections
z First, a uniform population of neural progenitors, the cells of the neural plate, are recruited from a large sheet of ectodermal cells. z Second, the cells of neural plate rapidly begin to acquire differentiated properties, giving rise to both immature neurons and glia cells. z Third, immature neurons migrate from zones of cell proliferation to their final positions and extend axons toward their target cells. A process of selective synapse formation is initiated. z Fourth, electrical and chemical signals passed across synapses can control patterns of connectivity and the phenotype of the neurons themselves. The neural plate folds in stages to form the neural tube. Folding of neural plate form the neural groove first. This is followed by dorsal closure of the neural folds to form the neural tube (next slide). The process of the neural tube maturation is called neurulation. The caudal region of the neural tube gives rise to the spinal cord, and the rostral region becomes the brain. The proliferation of rostral part of the neural tube initially forms three brain vesicles: the forebrain, the midbrain, and the hindbrain. 終腦(endbrain) 前腦(prosomere, forebrain) 間腦 (between-brain)
中腦(midbrain)
菱形腦(rhombomere, hindbrain)
chick embryo Three-vesicle stage Five-vesicle stage
cephalic flexure straighten out later (midbrain-hindbrain) cervical flexure (hindbrain-spinal cord) Six major regions of the mature central nervous system Inductive signals control neural cell differentiation z Inducing factors are signaling molecules provided by other cells. z The molecules that are activated or induced in the cells upon exposure to an inducing factor from another cell. A cell’s fate is determined in part by the signals to which it is exposed, which is largely a consequence of where it is originally located in the embryo, and in part by the gene expression profiles as a consequence of its developmental history. Competence zThe ability of the cell to respond to inductive signals. It depends on the precise repertory of receptors, transduction molecules, and transcription factors expressed by these cells. Neural plate is induced by signals from adjacent nonneuronal mesoderm z The differentiation of the neural plate from uncommitted ectoderm in amphibian embryos depends on signals secreted by a specialized group of cells later called the organizer region. z Dorsal lip of the blastopore destined to form the dorsal mesoderm was excised and transplanted underneath the ventral ectoderm of a host embryo, a region that normally gives rise to ventral epidermal tissue. The transplanted cells follow normal developmental program to generate mesoderm. However, the host ventral ectoderm formed a duplicate body axis that included a complete second nervous system. The organizer graft experiment done by Spemann and Mangold in 1924.
dorsal lip of the blastopore destined to form the dorsal mesoderm Neural induction involves inhibition of BMP signals z When early ectoderm is dissociated into single cells to prevent intercellular signaling and cultured without added factors, these single cells form neural tissue. z Bone morphogenetic proteins (BMPs), a group of TGF-β-related proteins, mediate the suppressive signal inhibiting ectodermal differentiation into neural tissues. z BMP signaling promotes the differentiation of ectoderm into epidermis. Cells expressing dominant negative mutant of BMP receptors differentiate into neural tissue. Follistatin, noggin, and chordin are endogenous neural inducers z Cells in the organizer region express three secreted proteins-follistatin, noggin, and chordin-each of which is able to induce ectoderm to differentiate into neural tissue. z All three proteins bind to BMPs and act as endogenous neural inducers. z The differentiation of neural plate cells triggered by inhibition of BMP signaling appears to involve the expression of transcription factors of the Sox gene family.
Neural plate is patterned along dorsoventral axis by signal from adjacent nonneuronal cell
z Mature spinal cord neurons process sensory input (dorsal half) and coordinate motor output (ventral half). z Motor neurons are generated lateral to the floor plate, a population of specialized glial cells in the ventral half of the neural tube. Interneurons are formed dorsal to the position of motor neurons. z In the dorsal half of neural tube, two types of cells form initially: neural crest cells that populate the PNS and specialized glial cells that form roof plate. Cells lateral to the roof plate differentiate into dorsal sensory interneurons. z SHH patterns the ventral neural tube. z BMP patterns the dorsal neural tube.
axial mesoderm/ notochord epidermal ectoderm flanking lateral edges of neural plate dorsal tips of neural fold
floor plate cells roof plate and adjacent dorsal neural tube floor plate
dorsal neural tube
floor plate z Sonic hedgehog (SHH) is a family member of secreted proteins related to Hedgehog, a gene that controls embryonic development of Drosophila. z SHH by itself is capable of inducing differentiation of floor plate cells, motor neurons, and different subclasses of ventral interneurons. Blockade of SHH functions eliminates the ability of notochord to induce all of the cell types normally generated in the ventral neural tube. MN: motor neuron SHH expression V1: ventral interneuron V2: ventral interneuron FP: floor plate floor plate
notochord z SHH acts not only as an inducer but also as a morphogen, the inductive signal that can direct different cell fates at different concentration thresholds. z A concentration gradient of SHH forms in ventral neural tube that is controlled by diffusion of SHH from the notochord and floor plate. z Inactive SHH precursor is cleaved autocatalytically by a serine protease-like activity contained within C- terminal domain of SHH itself. z Active N-terminal domain of SHH is covalently attached with lipophilic cholesterol. This modification tether most of the SHH to the surface of notochord and floor plate cells, while also allowing diffusion of small amounts of SHH. Binding to SHH to PTC releases SMO from the PTC/SMO heterodimeric receptor complex.
PTC: patched SMO: smoothened
transcription factor z BMP signals mediate the differentiation of dorsal neural tube cells including neural crest cells, roof plate cells, and dorsal interneurons. z BMPs activate dimeric receptors that are serine- threonine kinases. BMP binds to type II receptor, which in turn activates type I receptor. Type I receptor than phosphorylates SMAD proteins, leading to ultimate transcription of target genes (next slide). unphosphorylated cytoplasmic proteins Inductive Signaling in Dorsal and Ventral Neural Tube z Ventral patterning is regulated by the activities of a single protein SHH, which generates different cell types at different concentrations. z Dorsal patterning is regulated by several members of the BMP family, each of which may induce a particular set of cells. z Both inductive signaling is initially expressed by nonneural cells (epidermal ectoderm dorsally and notochord ventrally). Then these signals are transferred to specialized glial cells at midline of neural tube (roof plate dorsally and floor plate ventrally). z SHH induces formation of distinct classes of ventral neurons at different rostrocaudal levels. z At different levels of the hindbrain and midbrain, motor neurons (green), serotonergic neurons (blue), and dopaminergic neurons (purple) differentiate close to cells that express SHH. z In the telencephalon, the ventral or diecephalon, domain of SHH expression is close to the position of ventral forebrain interneurons (red). z The neural tissue induced by follistatin, noggin, and chordin appears to express genes that are characteristic of forebrain but not of more posterior tissue. z Fibroblast growth factor (FGF)-related secreted proteins and retinoic acid appear to be involved in the induction of posterior neural tissue. z Organization of motor neurons in developing hindbrain. z Neural tube is subdivided into repetitive segment units. The periodic swellings in hindbrain (rhombencephalon), termed rhombomeres, are fundamental to neuronal organization. Hindbrain is organized in segmental units by Hox genes z Hox genes control the identities of rhombomeres. These genes encode proteins with highly conserved 60-aa DNA binding domain called homeodomain. Homeodomain proteins are one class of transcription factors regulating developmental process of yeast, plants and mammals. z Hox genes in mammals comprise homeobox genes that are organized into four separate chromosomal complexes, each of which is located on a different chromosome. The clustered organization of Hox genes is conserved in flies and mammals. z Genes involved in patterning hindbrain are expressed segmentally. z Within hindbrain the anterior limit of expression of Hox genes appears to coincide with the boundaries of rhombomeres. z Hox gene expression is regulated by mechanisms intrinsic to the neural tube and by signals from surrounding mesodermal cells. z The selective expression of Hox genes within different rhombomeres in the hindbrain is itself regulated by other transcription factors. For example, the zinc finger protein Krox20 is expressed in rhobomeres 3 and 5 and controls the expression of Hox genes in these two rhombomeres. z Hox gene expression in the hindbrain is also regulated by the retinoic acid that is expressed in the mesodermal cells adjacent to the organizer region. Embryos treated with retinoic acid express Hox genes at more anterior regions of hindbrain; neurons in these regions acquire a more posterior identity. Mutations in Hox genes change motor neuron identity in the hindbrain. Trigeminal motor neurons are generated in r2 and migrate laterally, whereas facial motor neurons are generated in r4 and migrated caudally. The midbrain is patterned by signals from a neural organizing center z The midbrain lies beyond the rostral limit of Hox gene expression and in contrast to the hindbrain, is not subdivided into obvious segments. z Pattern of cells in the midbrain is controlled by the long-range action of signals from isthmus region, a secondary organizing center at the junction of the mesencephalon (2, midbrain) and metencephalon (3a, afterbrain). z Wnt-1 and FGF8 are secreted by isthmus cells to control the differentiation of the mesencephalon. z FGF8 signals control the polarity of mesencephalon. Grafting isthmus cells or cells expressing FGF8 in the posterior diencephalon causes surrounding cells to acquire a midbrain character. z Deletion of mesencephalon and metencephalon in Wnt1 mutant embryos. They are also deleted in the absence of En1/En2 genes. Rostrocaudal pattern of midbrain is controlled by homeodomain proteins z In the midbrain, the expression of two homeodomain proteins, engrailed 1 and 2, is normally graded in a caudal-to-rostral direction. z If the mesencephalon is reversed at a late stage with the expression of engrailed proteins, the cytoarchitecture of the tectum and the pattern of retinal axon innervation are inverted. Experimentally altering the gradient of engrailed proteins reproduced similar effects. z Embryonic forebrain is initially divided along its rostrocaudal axis into transversely organized domains or prosomeres. Prosomeres 1-3 → caudal part of diencephalon; prosomeres 4-6 → rostral diencephalon and telencephalon. Ventral region of rostral diencephalon gives rise to hypothalamus and basal ganglia. z The boundaries of prosomeres coincide with the expression of inductive signals and transcription factors. z SHH is expressed in zona limitans intrathalamica between prosomeres 2 and 3. Some neurons in the neocortex develop from cells that migrate from the striatal subdivision of the telencephalon. These striatal progenitors express two homeodomain proteins, DLX-1 and DLX-2. In mice lacking these proteins, striatal progenitors fail to migrate into the neocortex, resulting in depletion of γ- aminobutyric acid (GABA) neurons in neocortex.
VZ: ventricular zone SVZ: subventricular zone z The development of regional differentiation within the cortex has been examined in the primary somatosensory cortex of rodents, which contains discrete structures termed barrels. z Barrel formation depends on input from the periphery; their formation is disrupted if the whisker field in the skin is eliminated during development. When prospective visual cortex tissue is transplanted in place of the somatosensory cortex around time of birth, barrels form in the transplanted tissue in a pattern that closely resembles that of the normal somatosensory barrel field. Thus, many regions of cortex can develop features characteristic of specific areas, and new patterns are determined by local cues such as the inputs they receive. Transgenic mice expressing β-galactosidase reporter gene only in somatosensory cortex is generated. When somatosensory cortex is grafted into other regions of the cortex, the transplanted cells continue to express β- galactosidase despite their new location. This finding implicate the existence of intrinsic differences between cortical areas at early stages.