130 BICD Embryos, Genes, and Development
The left/right axis: Organ asymmetry in vertebrates
Heart on left side of chest cavity Spleen and pancreas on left side Major lobe of liver on right Lung asymmetry
The L/R axis: Morphological left/right asymmetry is apparent early in vertebrate development
... and molecular asymmetry even earlier
nodal mRNA
Chick embryo
Pathway for left/right asymmetry in mammals
"Nodal flow" created by cilia in Hensen s node appears to provide the cue for L/R asymmetry in mammals
Knockout mutation of the situs inversus viscerum (iv) gene encoding the ciliary motor protein dynein: Makes nodal cilia immotile Results in bilateral or absent expression of nodal and lefty-2 Randomizes the position (situs) of asymmetrical organs
Left-right Asymmetry -- 2005 Update
Recent advances in understanding left-right axis specification:
Evidence that nodal flow causes the leftward movement of membrane-bound vesicles containing Sonic hedgehog and retinoic acid New insight into how the rotation of nodal cilia can induce net leftward flow Strong evidence that the role of nodal cilia and nodal flow in left-right axis determination is conserved among vertebrates
Evidence that nodal flow causes the leftward movement of membrane-bound structures containing Sonic hedgehog and retinoic acid
Nature 435: 172-177 (2005)
"Nodal vesicular parcels" (NVPs) fragment at the left wall of the node, releasing their contents
New insight into how the rotation of nodal cilia can induce net leftward flow
PLoS Biology 3(8): e268 (2005)
Posterior tilt of cilia means surrounding fluid is dragged more efficiently on leftward stroke than on rightward stroke
Strong evidence that the role of nodal cilia and nodal flow in left-right axis determination is conserved among vertebrates
Okada et al. (2005). Mechanism of nodal flow: A conserved symmetry breaking event in left-right axis determination. Cell 121: 633-644. Essner al. et (2005). Kupffer s vesicle is a ciliated organ of asymmetry in the zebrafish embryo that initiates left-right development of the brain, heart and gut. Development 132: 1247-1260.
mouse
rabbit Red = posteriorly located cilia
medaka
Hox genes: Colinearity of chromosomal gene order and A/P expression pattern is conserved between flies and mammals
Conserved Hox gene clusters in fly and mouse
Hox gene expression patterns control the identity of vertebrae
Loss of Hoxc-8 gene function in mouse leads to a partial lumbar-tothoracic transformation of vertebral identity
Skeletal pattern and axes of the chick wing
Limb bud mesenchyme: Somitic myotome cells (muscle) and cells from somatic layer of lateral plate mesoderm (skeleton) create a limb bud
Apical Ectodermal Ridge (AER)
The AER controls proximal-distal growth and differentiation of the limb by interaction with limb mesoderm
Models for specification of the proximaldistal axis of the limb by limb mesoderm
Hypothesis that Hox genes specify limb regions along the P/D axis
Loss of Hox-11 paralogues in mouse deletes radius and ulna Wild-type Homozygosity for a mutation in HOXD-13 causes synpolydactyly
Hoxa-11Hoxd-11-
The zone of polarizing activity (ZPA) in the posterior limb mesoderm controls A/P patterning of the limb
Evidence that Sonic hedgehog has polarizing activity
Sonic Hedgehog in the ZPA
FGF10 expression in the LPM of the chick embryo
FGF8 expression in the AER
Induction and maintenance of the AER and ZPA
*
d H a n d
Wild-type
Wnt7a is required for D/V polarity of the mouse limb
Wnt7a-
vp: ventral footpad vt: ventral tendon dp: dorsal footpad dt: dorsal tendon
Model of major signaling interactions in the developing limb bud
1: FGF8 (AER) and dHand (posterior mesoderm) induce Shh (ZPA) 2: Shh induces FGFs in the AER by inducing Gremlin 3: Wnt7a (dorsal ectoderm) maintains Shh 4: Gradient of Shh creates gradient of activator and repressor forms of Gli3