ESTABLISHING
CELLULAR DIVERSITY IN THE EMBRYONIC BRAIN AND SPINAL CORD
Neural stem cells that give rise to
mature brain neurons and glia, with few exceptions, comprise a layer of cells
that lines the ventricular space of the neural tube throughout its entire
anterior-posterior extent. This layer, known either as the ependymal layer or
ventricular zone of the developing neuroepithelium is usually the unique
province of true neural stem cells: the proliferative cells in the
nervous system that divide symmetrically and slowly to yield additional stem
cells that have the capacity to generate all of the cell types in that region.
A distinct type of proliferative cell, the intermediate or transit amplifying
progenitor, is found in the mantle layer (also known as the
intermediate zone). In addition, many newly postmitotic neurons are also found
in the mantle layer. Finally, the outermost region of the neural tube
epithelium is referred to as the marginal layer, or zone. The marginal
zone has some post-mitotic neurons and glia and some nascent axonal and
dendritic processes from local differentiating neurons. In the spinal cord and
hindbrain (medulla and mesencephalon), the marginal zone is also usually the
site of axon pathways that grow from other regions of the brain to innervate
local target neurons. Thus these three neuroepithelial layers ependymal/ventricular, mantle/ intermediate, and
marginal maintain local neural stem cells, facilitate
neurogenesis, and support initial neuronal differentiation. The mantle and
marginal zones are also important for support of initial neuronal
differentiation and establishing initial connections between local dendrites and local or long-distance
axons.
The neural tube also acquires
regional distinctions in the posterior-anterior axis that reflect the ultimate
division of the spinal cord, hindbrain, mesencephalon, and diencephalon into
sensory and motor regions that either receive inputs from peripheral receptors
(sensory) and relay this information to additional brain regions, or send axons
to skeletal muscles or autonomic ganglia to regulate behavior and homeostasis.
From the most posterior aspect of the spinal cord through the anterior end of
the diencephalon, the neural tube becomes divided into posterior or alar and
anterior or basal plates. These zones are distinguished from one another
by a local groove, called the sulcus limitans, that indents the
ependymal/ventricular zone. Through-out the entire extent of the posterior or
alar plate, neurons are generated that become targets for sensory afferent
axons from the periphery or that relay sensory information from other brain
centers. Thus in the spinal cord, the medulla, the
mesencephalon, and the diencephalon, posterior plate derivatives become sensory
relay zones or distinct sensory relay nuclei. In the spinal cord, the
sensory relay zone is referred to as the posterior horn and eventually
becomes highly laminated in register with different classes of sensory input.
In the medulla, the posterior plate gives rise to sensory coordinating, or
relay nuclei for the cranial nerves. In the mesencephalon, the posterior
plate gives rise to the superior and inferior colliculi, which receive input
either directly from the eye (superior) or indirectly from the auditory nerve
(inferior). These two nuclei are crucial for integrating sensory information
with the initiation of motor commands. Finally, in the diencephalon, the
posterior plate gives rise to all of the thalamic sensory coordinating, or
relay nuclei for the senses: vision (lateral geniculate nucleus), audition
(medial geniculate nucleus), somatosensation (anterobasal complex), taste
(anterobasal complex), and olfaction (medioposterior nucleus). Throughout the
posterior region of the spinal cord, medulla, mesencephalon, and diencephalon,
the mantle zone becomes the location of axon tracts that carry sensory
afferent axons.
In parallel with the differentiation
of the posterior/ alar plate, the anterior/basal
plate yields groups of neurons whose axons project directly to striated muscles
(skeletal motor neurons), autonomic ganglia (preganglionic motor neurons),
cranial muscles largely derived from the neural crest (cranial motor neurons),
or whose axons project to skeletal, preganglionic, or cranial motor neurons to
provide CNS regulation of their commands to the peripheral muscles and glands.
The position of various anterior plate derivatives along the anterior-posterior
axis, from the spinal cord, through
medulla and mesencephalon, through the diencephalon, determines the type of
motor neuron that is generated.Thus throughout the entire spinal cord, most of
the motor neurons in the anterior horn or column are skeletal motor
neurons. In addition, in the thoracic spinal cord, preganglionic motor (or
visceral) neurons are generated in the lateral horn, approximately in
the region of the sulcus limitans. In the medulla, there are a variety of cranial
motor nuclei that have cranial motor nerves that project to the muscles of the
head and neck, the jaws, the tongue, and the eyes. In the mesencephalon, there
are a number of tegmental nuclei that influence motor function (including the
ventral tegmental area, or VTA, which has dopaminergic neurons), as well as the
red nucleus, whose neurons project to skeletal motor neurons that
regulate, among other things, gross arm movements. Finally, the basal plate of
the diencephalon becomes a collection of motor control nuclei of the
hypothalamus that project to preganglionic, visceral motor neurons that
regulate a broad range of homeostatic and reproductive functions. The mantle
zone of each region of the anterior plate develops into distinctive axon tracts
that primarily carry axons of motor control neurons that project from
higher centers (like the mesencephalon or hypothalamus) to motor neurons in the
medulla and spinal cord.
Thus based on the position of neural
stem cells in the ependymal/ventricular layer of the entire
rudimentary spinal cord, medulla, mesencephalon, and diencephalon, there is an
orderly specification of distinct sensory and motor neurons that serve distinct
regions of the body: the trunk, limbs, and viscera for the spinal cord; the
head, neck, and viscera for the medulla; mesencephalon, and diencephalon. This
consistent specification relies on the establishment of centers that provide
molecular signals to the posterior/alar and anterior/basal plate from the
posterior spinal cord through the anterior mesencephalon. At the anterior
midline is the floor plate, a thin region of neuroepithelial cells that
secretes the key signaling molecule sonic hedgehog as well as several other
signals to establish motor neuron identity. At the posterior midline is the roof
plate, which provides signals that similarly influence the genesis and
differentiation of sensory neurons. These include bone morphogenetic proteins
(BMPs), wingless/integration (WNT) signals, and retinoic acid. Accordingly, the
basic neuroanatomic and functional organization of the spinal cord, medulla,
mesencephalon, thalamus, and hypothalamus reflects the developmental position
and molecular signaling history of neural stem cells that generate the neurons
of each brain region.
