Development of the CNSDevelopment of the CNSPart 1Part 1

Andy Fischer, PhDAndy Fischer, PhDDepartment of NeuroscienceDepartment of Neuroscience

fischer.412@osu.edufischer.412@osu.edu

Development of the CNS part 1

(1) Identify the inductive cues that promote the formation of neural ectoderm from ectoderm and the cues that pattern different regions of the CNS.(2) Describe how all of the CNS is derived from the embryonic neuroepithelium, a homogeneous monolayer of cells. (3) Describe how all neurons and glia (except the microglia) are generated from neuroepithelial stem cells.(4) Describe how early during development neural stem cells are multipotent, capable of producing all types of neurons and glia, and that as development proceeds the potential of the stem cells is gradually restricted until the final rounds of cell division produce only glial cells.(5) Describe how neural stem cells proliferate to generate new stem cells or postmitotic neuroblastic cells which migrate to locations within the CNS or PNS to complete the process of differentiation.(6) Describe why there is a wide window of opportunity during development to disrupt any of the numerous events that are necessary to give rise to a single neuron and its numerous connections within the CNS.(7) Identify the cell types that are derived from the neural crest stem cells. (8) Identify disorders that arise if embryonic neural development is disrupted.

Learning Objectives

Development of neurons is complicated

Hundreds of steps are required for proper neuronal differentiation and development

Neural stem cell Mature neuron

Outline neurodevelopment part 1

Topics to be covered (part 1)

(1) Formation of the neural tube

(3) Neural crest cells and some of the crest-derived cell types

(5) Developmental defects of the central nervous system

(2) Neural stem cells – multipotency – produce almost all cell types within the central nervous system

(4) Development of anterior neural structures – cortex & cerebellum

Development of the human embryo. -The initial cell divisions produce blastomeres.

-After multiple divisions, the embryo is called a blastocyst and develops an inner cell mass and an outer layer of cells.

-The inner cell mass will develop into the embryo, while the outer cells will contribute to the placenta. -After implantation, the embryo elongates and forms a primitive streak.

-The primitive streak is a line of cells migrating into the blastocoel that will form the mesoderm, and the neural tube will be derived from the ectoderm overlying the involuting mesoderm.

- The tube rolls up and forms the brain and spinal cord; this process of neural tube formation is very similar across vertebrate species.

Review of early embryonic development

Induction of neural ectoderm

Model of neural induction.

-The involuting mesodermal cells release several molecules that block the BMP signals between ectodermal cells.

- Chordin, noggin, and follistatin all block the activation of receptors by the BMPs from the ectoderm and thereby allow (or dis-inhibit) the ectoderm to form neural tissues.

- In other words, a dorsal region of ectoderm is “induced” to develop as neural tissue, ultimately generating the brain, spinal cord, and most of the peripheral nervous system.

Chd = chordin, Ng = noggin , Flst = follistatin, BMP = Bone morphogenetic protein

Neural ectoderm from ectoderm

                                                                                                                                                                                                        

                  

The neural plate beginning neural groove at about 18 days of development (A) and the neural groove 2 days later (B), shortly before the neural tube begins to close. (From

Arey LB: Developmental anatomy, ed 4, Philadelphia, 1941, WB Saunders.)

Neural tube formation

                                                                                                                                                                                                                          

A, Neural folds begin to fuse at the cervical level of the future spinal cord at about day 21. B, Tube fusion “zippers-up” in both rostral and caudal directions. C, By day 24, the rostral end of the neural tube has closed; the caudal end will close about 2 days later. Mesoderm-derived somites form most of the vertebral column, as well as segmental structures such as skeletal muscle. (From Arey LB: Developmental anatomy, ed 4, Philadelphia, 1941, WB Saunders

somite

Neural tube formation - cont’d

FIGURE 2.22 The organization of the neural tube emerges soon after closure.

-The most ventral part of the neural tube becomes flattened into a distinct floorplate.

-The most dorsal aspect of the neural tube develops into a tissue known as the roof plate.

- A groove, the sulcus limitans, forms between the dorsal and ventral parts of the neural tube along most of its length.

Patterning of the neural tube

                                                                                                                                                                                                                          

Sulcus limitans and alar and basal plates. A, Neural tube during the fourth week. B, Embryonic spinal cord during the sixth week. Dorsal root ganglion (DRG) cells, derived from the neural crest, send their central processes into the spinal cord to terminate mainly on alar plate (AP) cells; basal

plate (BP) cells become motor neurons, whose axons exit in the ventral roots. C, Adult spinal cord.

Patterning of the neural tube – cont’d

The Neural Tube

Figure 19.8C

Wall ofneural tube

Central canal

Neural crest-deriveddorsal root ganglion

Cross section of the neural tube

dorsal

ventral

Neural Tube Wall & neural stem cells

Figure 19.7

Neuroepithelial cell(neural stem cell)

Neuroblast

Central canal Pial surface

Neurogenesis in the neural tube. -The proliferating neural stem cells are in S-phase when the cell bodies are located in central region of the wall of the neural tube. -The stem cells undergo mitosis at the ventricular surface near the central cannal. - When daughter cells exit the cell cycle and begin to differentiate as neurons, they migrate radially from the ventricular (ependymal) zone to the mantle zone. -The progenitor cells span the thickness of the neural tube.-The nuclei return to the ventricular surface during G2 and the M-phase of the cell cycle always occurs at the ventricular surface.

Proliferation of Neural Stem Cells

Dorsal-ventral patterning of the neural tube by BMPs and Shh

                                                                                                                                     

Dorsal-ventral patterning of the spinal cord by concentration gradients of secreted signaling proteins.

A, Midline mesoderm and later the notochord produce a signaling protein - sonic hedgehog (SHH). Simultaneously, ectoderm adjacent to the neural plate produces bone morphogenetic proteins (BMPs).

B, Under the continued influence of the notochord, cells near the ventral midline of the neural groove begin to express SHH themselves. Ectoderm near the crests of the neural folds continues to produce BMPs.

C, After the neural tube closes, cells near the dorsal midline produce BMPs, continuing the opposing SHH-BMP concentration gradients. (Based on a drawing in Tanabe Y, Jessell TM: Science 274:1115, 1996.)

Patterning of the neural tube

Dorsal ventral patterning – cont’d

Dorsal-ventral patterning of the neural tube.

- In addition to BMPs, Wnt’s are expressed by cells in the dorsal ascpects of the neural tube cells later in development.

- Like BMPs, Wnts are also TGF-beta-related molecules.

-These two signals antagonize one another, and through this antagonism they set up opposing gradients that control both the polarity of spinal cord differentiation and the amount of spinal cord tissue that differentiates into dorsal, ventral, and intermediate cell types.

Differentiation in the neural tube is dependent on factors derived from adjacent, nonneural tissues. B: If the notochord, a mesoderm-derived structure, is removed prior to neural tube closure, the ventral neural tube fails pattern properly, i.e. no floorplate (blue) or spinal motoneurons (red). Thus, the notochord is necessary for the development of the ventral neural tube fates.

C: If an additional notochord is transplanted to the lateral part of the neural tube, a new floorplate is induced adjacent to the transplanted notochord and ecotopic motorneurons form adjacent to the ectopic floorplate. Thus, the notochord is sufficient to pattern ventral spinal cord.

The notochord and ventral patterning

The potential of stem cellsbecomes reduced during

the normal course of development

David J. Anderson et al. Nature Medicine 7, 393 - 395 (2001)

A review of stem cells

-The “early” neural stem cells of the neural tube generate an enormous number of progeny.

-The stem cells undergo symmetric cell divisions to produce additional stem cells as well as progenitor cells.

-The progenitor cells are capable of a limited number of cell divisions.

-The late progenitor cells generate both neurons, oligodendrocytes and astrocytes.

- Certain regions of the nervous system, particularly the developing optic nerve, have astrocytes and oligodendrocytes that share a common progenitor, known as the O2A glial progenitor.

-By contrast, in the spinal cord, motor neurons and oligodendrocytes share a common progenitor.

-Thus, the lineage relationships shown varies depending on the region of the CNS.

Lineage of neural stem cells

Neural stem cells give rise to most cell types in the CNS

NeuralStem cells give rise to

most, but not all types of cells in CNS

Mesenchymal stem cells

-Ependymal cells-Choroid plexus

inhibitionof

neurogenesis

Neural stem cells in different regions along the neural tube tend to generate different types of neurons

Ventral diencephalonStem cells

Anterior telencephalonStem cells

Dorsal RhombencephalonStem cells

Neural stem cells have different “potentials” in different regions of the developing neural tube

Differentiation of different cells types

Determination of different neuronal cell types is highly ordered.

- For example, in the retina a progenitor cell in the neuroepithelium divides many times and gives rise to progeny that include all the major cell types of the retina. -Different neuronal types tend to be born (generated) at different developmental times.

- Projection neurons or “born” first and glia are ‘born” last

-This process is guided by both secreted factors and cell-intrinsic transcription factors

Retinal stem cell

From: Santiago Ramon y Cajal, The Structure of the retina, about 100 years ago

For example, many different For example, many different types of neurons can arise types of neurons can arise

from a retinal stem cell from a retinal stem cell

A neural stem cell can produce a wide variety of

neuronal types

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