Download PG1007 Lecture 7 Anterior-Posterior Patterning, HOX Genes and

TR056/PG1007 Lecture 7 Regula5on of Pa9erning Dr. Neil Docherty My Teaching Objec/ves • To emphasise that the body plan should be considered in terms
of the three axes
• To relate the role of model systems in the story of identifying
the genes controlling anterior-posterior patterning (A-P) in the
embryo
• To describe the concept of colinearity with regard to HOX gene
expression patterns and illustrate how exogenous retinoids
may disrupt this pattern
• To briefly consider the main concepts of D-V and L-R patterning
Complexity of Body Plan Gametes
Zygote
Diverse final body plans all pass through
these stages under the control of
patterning genes which are fundamentally
conserved through the evolutionary tree
Blastocyst
Embryo
THE 3 AXES
1.  Anterior-posterior/head-tail (cranial-caudal)
2.  Dorso-ventral
3.  Left-right (bilateral body plan chordata)
Foetus
The Body Axes
R
L
Cr
Ca
V
D
Establishment of these axes depends on site specific gene
expression patterns
Origin of Our Understanding of
Patterning Along The Anterior-Posterior Axis
The master regulators of patterning along this axis are the
HOX genes (transcription factors)
The story of the elucidation of the role of these genes
begins with the original description of the phenomenon of
homeosis
“The essential phenomenon is not that there has
merely been a change, but that something has
changed into the likeness of something else”
William Bateson 1894
Drosophila Melanogaster and the Discovery of Genes Controlling Homeo/c Transi/on The Nobel Prize in Physiology or Medicine
1995
-Edward B. Lewis
-Christiane Nüsslein-Volhard
-Eric F. Wieschaus
"for their discoveries concerning the genetic control of
early embryonic development".
Lewis identified that mutations in a gene complex on
chromosome 3 were responsible for homeotic duplication of
wings in mutant flies
HOX-­‐Genes • In mammals HOX genes
arranged in 4 sets of 13
Location of Lewis’s Across 4 chromosomes
(7-A 17-B 12-C D-2)
wing mutation
• Each gene includes a
Homeobox consensus
• This sequence codes for a
homeodomain (60a/a)
• The homeodomain binds to a
TAAT…. enhancer on
regulatory regions of target
genes
Paralogous
groups
3’ early
5’ late
Expression of HOX Genes Along Dorsal Axis Note that HOX expression
patterns show sharp boundaries
cranially and graded boundaries
caudally
This leads to different doses of HOX
genes at given levels and the
staggered complete absence of individual
HOX genes at the cranial end
Evidence that a HOX Code Causes Axis Specifica/on 1.  Gene knockout experiments
2.  Comparative Anatomy
3.  Retinoic Acid Teratogenesis
Retinoic Acid Teratogenesis
Retinoic acid is normally produced in the
embryo (node) and constitutes one of the elements controlling HOX gene expression
Excess maternally derived retinol can be metabolised In the embryo to produce
excess retinoic acid
This interferes with the gradients of retinoic acid along the A-P axis
This can lead to homeotic transitions
Retinoic Acid-Regulation of
HOX Gene Expression
Left-Right Asymmetry
Consider the fact that overall
external symmetry of the body
is not matched in the visceral
organs
How can this be?
The answer in part may be due
to cilia and the asymmetric
accumulation of nodal protein
secreted from the primitive
node
Mutations in key cilial motor
proteins produce situs
inversus as well as respiratory
disease in Kartagener’s
Syndrome
Bilateral Assymetry
The Dorsal-Ventral Axis
This axis is specified by the separation of the inner cell mass into
Embryonic and Abembryonic regions
This develops perpendicular to the animal-vegetal pole of the
fertilised egg
D-V specifc gene expression then is maintained by the effect
of signals from the notochord on the overlying ectoderm
Notochord derived
signals
Today’s Learning Objec/ves Your learning from today should focus on being able to;
1)  Describe the body plan in terms of the three axes
2)  Relate how the phenomena of segmentation and homeosis
in model systems helped explain anterior-posterior patterning
(A-P) in the human embryo
3) Explain the concept of colinearity with regard to HOX gene
expression patterns and illustrate how endogenous retinoids
control this and how exogenous retinoids therefore act as
teratogens.