Hegdehog knockout mice

1 . Defects in limb development

2 . Defects in digit formation along the anteroposterior axis

Loss of function Hh mutations in Dorsophila –

Fly embryo is covered with pointy denticles on its cuticle
( segment polarity )

Loss of Hedgehog signaling

Holoprosencephaly (Development of midline structures disrupted )
Cyclopia
Defects in brain development

Vertebrates have three homologues of Hh :

Sonic hedgehog ( shh ) Expressed in Sertoli cells (defective
spermatogenesis in KO)
Involved in motor neuron generation only from the ventral portion of
the neural tube
Desert Hedgehog ( dhh ) Expressed in the gut
Indian hedgehog ( ihh ) Expressed in gut and cartilage and is
important for postnatal bone growth
Different concentrations of Hh induce different
neuronal cell types in the ventral spinal cord .
 Cyclopia

Cerebral hemispheres were fused

Veratrum californicum inhibits cholesterol

biosynthesis
jervine and cyclopamine also inhibit cholesterol
biosynthesis
Processing of Hedgehog protein
 Patche
d

_
PKA
CK1
GSK3 Slimb
p p
Ci
Cos2 p p Fu
Smoothened

Proteasomal
degradation

Fu Kinase Ci75
Cos2 (costal) kinesin related motor
protein
_
Nucleus
 P
P
Cos2
P P
P P
Fu
P

Ci

CBP
Patched
Wnt
Nucleus Myc
Regulation of Hh signalling

Feedback control at the level of Patched transcription

Vertebrate homologues of the Ci protein in Drosophila are the Gli proteins

Tuncation in the the actiavtor region of the GLI3 protein results in makin
it function like a repressor resulting in formation of extra digits and
poor development of Pitutary gland,
Hypothalamus, anus and kidenys and the infants die soon after birth
( Pallister-Hall syndrome)