Transcript the HOX Genes!!

Learning Outcomes
1. Understand the molecular mechanisms underlying
early embryonic development in vertebrates.
2. Explain, in general, how organizers function to
pattern the forming axes of the early embryo.
3. Appreciate the conservation of molecular
mechanisms controlling body plan development in
different organisms: the case of homeotic genes.
4. Colinearity of the homeotic genes in man.
Outline
Developmental processes occurring during vertebrate development
Axes formation
-Signalling centres
Left right asymmetry
Anterior-posterior axis formation
Animals must be specified in
three dimensions
The germ layers are created during gastrulation
Lecture E01
The germ layers form different tissues
Basic morphogenic processes
are similar between animals
Gastrulation in a fly
FlyBase
Development in vertebrates is based on cell-cell interactions:
groups of cells called organizing centres emit instructive signals
that induce and pattern surrounding tissues.
The concentration gradient of the (signal) morphogen induces
multiple cell choices. (E05)
Organisers are involved in body axis formation in vertebrates
Signalling centres instruct surrounding cells to form tissues
Node graft
Two headed cow...
Genetic determinants involved in body axis formation in mammals
The major signalling centre in vertebrates is the node
Node
Chicken
Human
Question: How does the node
pattern?
Genetic determinants involved in body axis formation in mammals
Organisers ‘pattern’ surrounding cells and
tissues by secreting
signaling molecules (proteins)
Node cells secretes nodal and noggin and FGF
Nodal
FGF
Cells signalling through transmembrane receptors
FGF
Extracellular
FGFR
Intracellular
SHC
Grb2
RAS
SOS
RAF
MEK
P
MAPK
Genetic determinants involved in body axis formation in mammals:
Neural tissue
Signalling centres instruct surrounding cells to form tissues
Node or FGF protein
Overlying tissues form a neural tube
Gradients of secreted proteins produce the different germ layers
Left-right asymmetry of internal organs
Lungs
Heart
Gut looping
Liver
http://mekhala.blogspot.com/2007_11_25_archive.html
Left-right patterning
asymmetric signalling from the node
The expression of genes
on the left side of the
embryo leads to a cascade
of gene expression and
morphogenic changes
Nodal
Nodal
Pitx2
Gut looping, heart looping
chick
In situ hybridisations of left-right asymmetry genes
Node and cilia
How to break symmetry
The node spins
anterior
R
L
posterior
Loss of left-right asymmetry leads to disease
Situs inversus
•Named for mutations that
revealed existence
•Bithorax – part of haltere on
3rd thoracic segment is
transformed into part of a wing
•Antennapedia – dominant
mutations transform
antennae into legs
•Homeotic mutation is the
transformation of one
segment into another related one
Homeotic
genes
3’
5’
Colinearity: location on the chromosome corresponds
to the spatial expression pattern
Temporal and spatial colinearity: order of Hox genes on the
chromosome follows the antero-posterior body axis.
How do we get anterior-posterior axis: the HOX Genes!!
Veraksa, Del Campo &
McGinnis.
2000. Mol. Genet. Metab.,
69, 85-100.
Combinations of Hox genes specify the development
of the anterior-posterior axis
Embryonic structures
Adult organs
Hox gene expression follows the somite bondaries
Film of somitogenesis
When Something Goes Wrong…
*
Thoracic vertebra
Extra rib
Lumbar vertebra
The function of Homeotic genes in mammals is similar to in flies: the KO of
hoxc8 in mouse causes an homeotic transformation: the first lumbar vertebra
forms a rib.
Summary: patterning of the vertebrate axial body plan
gastrulation and organizer activity
the four Hox gene complexes are expressed along the antero-posterior axis
Hox gene expression establishes positional identity for mesoderm, endoderm, and ectoderm
mesoderm develops into notochord,
somites, and lateral plate mesoderm
mesoderm induces neural plate
from ectoderm
somite develops into sclerotome
and dermomyotome
notochord patterns neural tube
Diseases associated with Hox gene mutations
1. Hand-foot-genital syndrome
(Hox A11-13 deletion)
2. Synpolydactyly (HoxD13
deletion)
3. Cleft palate
4. Brain abnormalities
5. Leukemia (Hox D4)
6. Retinoic acid, which causes
birth defects, affects Hox
genes
Polydactyly
Teratology Lecture
Hox genes and vertebrate segment identity
•Hox gene mutations lead to subtle phenotypes
Why??
•Hox genes are used over and over again in the developing
embryo
>>>Multiple phenotypes, multiple cancers
Reference book: Developmental Biology, Gilbert