Download Molecular Neuro Lecture 28 revised 04/10 Introduction to Neural

Molecular Neuro Lecture 28
revised 04/10
Introduction to Neural Development
We have studied the functions of some of the enormous diversity of cell types that comprise the
nervous system. Diverse in their morphology and biochemical properties (receptors, neurotransmitters,
etc.), these cells are connected in precise ways- this is necessary to create a network that has
sophisticated sensory reception, processing, and motor behavior capability
How do these cells come into being during the life of the organism, and how are they connected
together to form such precise circuits with such impressive capabilities?
Neurons differ from each other in many ways, but one of the major keys to making them different is
that they express different subsets of the set of proteins coded for by the genome. What causes a given
neuron type to express a particular set of proteins? One of the primary regulatory mechanisms is the
combination of transcription factors expressed by that type of neuron, which in turn regulate
transcription such that a distinct set of mRNAs is expressed. Thus, in our discussion of development,
one of our focuses is how cells in the developing nervous system are specified to express a particular
“combinatorial code” of transcription factors.
The nervous system develops through a series of steps...in some cases more than one step occurs
simultaneously or in a different order from what follows, but it is useful to consider them separately in the
context of studying the molecules important in each step. The general order of events:
1-establishment of tissue that will give rise to the nervous system (neural tube; ectodermal placodes)
2-regional specification of neural tissue (anterior vs posterior; dorsal vs ventral)
3-Differentiation of neurons (and glia) from undifferentiated precursors
4-Migration of neurons (and glia) to their final positions in the animal
5-axonal/dendritic outgrowth and pathfinding
6- synapse formation/elimination; regulation of neuronal survival
7-modification of synaptic strength; ongoing plasticity of synapses and connectivity
Where does the tissue that gives rise to the nervous system come from?
vertebrate embryos- 3 different cell layers are established by the process of gastrulation- ectoderm,
mesoderm, endoderm
gastrulation is a series of cell movements- the outcome of which is to cause the endoderm to be on the
inside of the embryo, the ectoderm on the outside, and the mesoderm to be located between these two
layers
Fig 10.39, 10.44 in .pdf
Gastrulation also defines the anterior/posterior axes; the first cells to invaginate during gastrulation
become anterior mesodermal cells
some of the mesodermal cells that invaginate during gastrulation form the notochord and prechordal
mesoderm
invaginate first thru primitive pit, which becomes primitive streak as gastrulation continues
Gastrulation animations: http://learningobjects.wesleyan.edu/gastrulation/animations.php?ani=3D
Neurulation is the formation of the neural tube, which gives rise to both the spinal cord and the brain. A
hollow, dorsal neural tube is a hallmark of all vertebrate embryos.
Neurulation begins with the formation of a neural plate, a thickening of the ectodermal covering of
the embryo, caused when cuboidal epithelial cells become columnar. Then the edges of the plate fold
and rise, meeting in the midline to form a tube. Fig 22.1
As a result of the neurulation process, the apical surface of the epithelial cells is inside, facing the
lumen. Failure of the neural tube to close results in major developmental defects -- anencephaly if the
anterior neural tube fails to close (forebrain degenerates) and spina bifida if posterior closure is
defective. Not uncommon, 1/500 live births
Mechanical details of neurulation -Molecular mechanisms
--shape changes of cells (e.g. heightening, wedge shape) rely on cytoskeletal changes (colchicine
blocks elongation- microtubules; cytochalasin prevents apical constriction- actin)
--ectoderm initially expresses E-cadherin, presumptive neural cells stop expressing, neural tube cells
begin expressing N-cadherin, neural crest cells migrate away- selective affinities
Neurulation animation: http://learningobjects.wesleyan.edu/neurulation/animation.php
Neural Crest – a vertebrate-specific, migrational cell type formed during neurulation
Origin of neural crest: Fig 22.2
During neurulation, the neural cells at the tips of the neural folds come to lie between the dorsal
neural tube and the overlying epidermis. These cells become the neural crest cells.
The juxtaposition of neural plate and epidermis determines the site of the neural crest. Both
epidermis and neural plate are capable of giving rise to neural crest cells.
Derivatives of the neural crest
The neural crest gives rise to many different types of cells throughout the body. Strikingly, this
includes sensory neurons, autonomic neurons (sympathetic and parasympathetic), Schwann cells, and
melanocytes (responsible for pigmentation of the skin)
Determination of neural crest cells : Is fate of individual neural crest cells already determined when
they leave neural tube? Or, are they multipotent?
These questions were addressed with two techniques
1) Clonal analysis : this technique allows identification of the types of cells that a single dividing cell
can make.
2) Transplantations
--heterochronic: different time (same place) and heterotopic: different place (same time).
The overall picture suggests that neural crest cells start out multipotent for the most part, but that their
potency is restricted over time, and is also impacted by the molecules that it sees in its environment.
Fate of the cells relates to their distinct migratory paths and the signals they are exposed to (see fig.
21.2)
after neurulation, the notochord and the mesoderm just anterior to it (prechordal mesoderm) are key
players in regional specification of the nervous system
notochord defines midline (left/right)
notochord sends signals to overlying ectoderm important in specifying it as neural- i.e. distinct from
the surrounding ectoderm which primarily becomes epidermis
in addition to the “vertical” mesoderm signals, there is evidence that signals that are lateral in plane of
ectoderm are important in specification (Keller expts)
What causes neural identity?
Ali Hemmati-Brevanlou’s Xenopus ectoderm dispersal expts- neural as a default state; inhibition of
TGFb signalling results in neuronal differentiation of primitive ectoderm; molecules such as chordin
and noggin that act to inhibit TGFb signaling implicated as important in neural induction
Neurogenins, NeuroD- bHLH txn factors; sufficient to cause neural differentiation of ectoderm; loss of
fxn blocks neural diffn of specific cranial ganglia neurons deriving from neural crest or placodal
precursors; could be similar molecules or combination of neurogenins specifies cns neurons as neurons
Establishing regional identity in the neural tube
First- the names of the A/P regions of the developing neural tube
distinctive bulges and folds give landmarks, fig. 22.5
rostral to caudal:
divisions and some of what they become (fig. 22.5):
prosencephalon -> telencephalon, diencephalon
rhombencephalon -> metencephalon, myencephalon
telencephalon- cerebral cortex, hippocampus, striatum, basal forebrain nuclei, olfactory bulb
diencephalon- thalamus, hypothalamus, optic cups
metencephalon- cerebellum, pons
myelencephalon- medulla
spinal cord
Anterior/Posterior regional specification in the neural tube- signaling events-
mesoderm of notochord/prechordal plate- vertical signals
there are also planar signals- in plane of neuroectoderm
embryo manipulations indicate that both types of signals appear to operate; expts of Spemann; Keller
what are the A/P regionalization signals? retinoic acid, secreted proteins including Wnts, FGFs
thus a set of signals relevant to cancer biology and elsewhere in developmental biology are important
in regionalizing the neural tube in the A/P and D/V axes- review of their receptors and transcription
regulation mechanisms is in Fig. 22.3
What determines regional identity in the A/P axis?
Several regionally expressed transcription factors implicated in specifying regional identity in the
neural tube:
Hox genes- brainstem, spinal cord; these are homeodomain transcription factors
Other homeobox-containing genes: e.g. Emx 1, 2, Dlx 1, etc., in forebrain, En-1/2- cerebellumnot part of the Hox complexes
fork head like genes (winged helix), e.g. BF-1, 2
Zn-finger transcription factors (e.g. Pax genes)
See drosophila figure; fig. 22.6- genetic studies of Drosophila development lead to identification of
many of the genes important in human brain development!
Interestingly, we seem to be segmented similarly to flies, just not as obviously- but think of the
vertebrae, dorsal root ganglia and spinal nerves, and cranial nerves (see the fig. in Box D,
rhombomeres).
What do A/P regionalization signals cause?
expression of specific transcription factors in A/P domains;
also expression of some signaling molecules in specific A/P domains (Wnts, FGF8); these
participate in subsequent signaling cascades that lead to further refinement in the specification of
identity
expression domains often begin/end with the bulges and folds- anatomical segmentation- of the
neural tube;
in hindbrain segmentation especially apparent; these also relate to cranial nerves and ganglia
note- a given rhombomere expresses a particular combinatorial code of transcription factors!