Lecture 2 - Early Development of the Nervous System Flashcards
Gastrulation
Invagination at specific site in the blastula leads to the formation of the three different tissue layers (ectoderm, mesoderm, endoderm)
Gastrulation defines the
midline, anterior-posterior and dorsal-ventral axes of the embryo
By the end of gastrulation
the midline of the embryo is defined, defined by formation of the notochord, critical for formation of all tissue including the CNS
When does early neurulation start?
At around 18 days
Early Neurulation is coincident with
gastrulation signaling events, the neural ectoderm is induced.
Notochord formation is
central to gastrulation
How is notochord formation central to gastrulation?
by defining the midline of the embryo and inducing the formation of neural ectoderm.
What is the very first event in neurogenesis?
Early neurulation
Neural ectoderm are
the neural precursor cells
How do you go from ectoderm to epidermis?
BMPs
How do you go from ectoderm to neuroectoderm?
Noggin/chordin
BMPs
Bone morphogenic protein (BMPs) subclass of the TGFβ (transforming growth factor beta) family
What are BMPs produced by?
surrounding tissue (mesoderm, etc.).
What do BMPs do?
they push ectoderm towards an epidermal state
Factors that inhibit BMP signaling are produced by
the notochord (Chordin, Noggin, etc.) and therefore block BMP signaling in ectodermal cells overlying the notochord (midline cells).
Blocking of BMP signaling does what?
induces cells to take on a neural fate
What is the default path for ectoderm?
neural fate can be seen as the default (in the absence of signaling cells will adopt a neural fate). For example if ectodermal pecursor cells are isolated and grown in a dish, they become neurons.
What do BMPs bind to?
receptor serine kinases and a SMAD complex
What happens after BMP binds to the receptor serine kinases?
The SMAD is transported to the nucleus to mediate transcription.
BMP activity drives formation of
epidermis.
Where are Chordin, Noggin and Follistatin produced?
in the notochord
What do Chordin, Noggin and Follistatin do?
they inhibit BMP signaling and lead to neural induction.
Neural inducers act as inhibitors of
BMPs, Nodal and Wnt signaling promote embryonic stem cell differentiation to committed neural stem cells.
Stimulation of what also induces neural stem cell formation.
retinoic acid (RA), fibroblast growth factor (FGF) and insulin-like growth factor (IGF)
What are required for neural induction?
Coordination of multiple signaling pathways
In neural induction, what comes first – FGF or BMP?
FGF signaling precedes BMP inhibition during neural induction.
FGF
fibroblast growth factor (FGF) stimulation increases production of Noggin, which in turn inhibits BMP signaling.
What happens after neural induction?
the lateral margins of the neural plate fold inward to form the neural tube. This proceeds very rapidly.
Cells that make up the neural tube are
neural stem cells.
What are the distinct areas that are noted in the formation of the neural tube?
the floor plate and neural crest
What happens as the neural plate closes to form the neural tube?
the neural crest pinches off (these will contribute to the formation of other cell types) and the roof plate forms.
From where does the neural tube close?
from the middle both anteriorly and posteriorly (think of a zipper running in both directions).
Neural tube closure is sensitive to
nutrition and environmental toxins
What is important to neural tube closure regarding nutrition?
Folic acid is particularly important. B-complex vitamins in the first few weeks of pregnancy decrease neural tube closure defects. The exact mechanisms by which folic acid works in unclear
NTDs
Neural tube closure defects (NTDs) 1) spina bifida 2) Anencephaly and holoprosenchephaly
What is the most common NTD?
1 in every 1000 births worldwide (one of the most common birth defects), 3.5 out of every 10,000 in US)
What is spina bifida?
Failure of the posterior end of the neural tube to close (spinal cord).
Anencephaly and holoprosenchephaly
1) 1 in 68,000 and 1 in 16,000 respectively 2) Represents failure of the anterior neural tube to close. Lack prosencephalon (forebrain). 3) Typically deadly.
What happens to the Neural Crest as the neural tube closes?
the Neural crest pinches off giving rise to: 1) Cranial Neural Crest 2) Trunk Neural Crest 3) Vagal and Sacral Neural Crest 4) Cardiac Neural Crest
Cranial Neural Crest
Cranial ganglia, bones and cartilage in face and head
Trunk Neural Crest
DRGs, sympathetic ganglia, adrenal medulla, melanocytes
Vagal and Sacral Neural Crest
Parasympathetic ganglia
Cardiac Neural Crest
Cartilage, melanocytes and neurons of the pharyngeal arches, regions of the heart.
Notochord induces
overlaying ectoderm into neural ectoderm (by inhibition of BMP signaling) and formation of the neural plate and neural groove (Shh dependent)
Neural tube closure
begins in the middle of the embryo and proceeds in both the anterior and posterior directions
Defects in neural tube closure leads to
anencephaly and spina bifida
Neural crest pinches off when
neural tube is formed and gives rise to cells in the peripheral nervous system
Dorsal Ventral Patterning
patterning makes cells in one different from cells in another area
Ventral signal
(motor) is secreted Sonic Hedgehog (Shh)
Dorsal signal
(sensory) is secreted by TGF betas (mainly BMPs)
What leads to the neuronal diversity along the dorsal / ventral axis?
More complex combinations of signaling through convergence of signaling pathways contribute to the remarkable neuronal diversity along the D/V axis primarily involving FGF and RA signaling
How is cellular and structural diversity created on the dorsal-ventral axis in the CNS?
1) Ventral Signal (motor) is secreted Sonic Hedgehog. 2) Dorsal Signal (sensory) is secreted TGF betas (mainly BMPs). 3) More complex combinations of signaling through convergence of signaling pathways contribute to the remarkable neuronal diversity along
What produces dorsal-ventral polarity?
High sonic hedgehog (Shh) expression in the notochord and roof plate and its absence in the roof plate
What does Shh bind to?
In the ventral neural tube sonic hedgehog (Shh) binds to Patched (PTC) and relieves the PTC-dependent inhibition of Smoothened (SMO).
SMO
(smoothened) activates the Gli class of zinc finger transcription factors.
Gli
induces transcription and leads to a ventral (motor neuron) cell fate.