Hedgehog Signaling in Animal Development and Human Disease 223
into right and left hemispheres. As in Shh mutant mice, alobar HPE in
humans is often accompanied by cyclopia, a primitive nasal structure,
and midline clefting. The striking similarity of Shh deficient mice to
human HPE quickly led to the identification of SHH mutations in both
familial and sporadic HPE (Roessler et al. 1996).
The majority of SHH mutations in HPE patients result in amino acid
substitutions rather than premature stop codons (Roessler et al. 1996;
Roessler et al. 1997). These mutations are predicted to reduce SHH
function, in part by affecting a critical aspect of its biosynthesis. Normally, Hh proteins are synthesized as precursors that are cleaved by an
autocatalytic reaction into N-terminal (Hh-N) and C-terminal fragments
(Hh-C) (Lee et al. 1994; Bumcrot et al. 1995; Valentini et al. 1997). All
of the signaling activity appears to reside in the highly conserved Hh-N
(Porter et al. 1995). Hh-C, while devoid of signaling activity, possesses
an enzymatic activity that is responsible for Hh self-cleavage (Lee et al.
1994; Porter et al. 1995). At least half of the HPE mutations occur in
SHH-C and may prevent SHH from undergoing the cleavage reaction
(Roessler et al. 1997). This is consistent with work in Drosophila where
mutations in Hh-C impair Hh maturation and function (Porter et al.
1995). Recent evidence implicating cholesterol in Hh signaling sheds
further light on the nature of these mutations.
12.5 The Role of Cholesterol in Hh Signaling
12.5.1 Attachment of Cholesterol to Hh
Cholesterol is important in two distinct aspects of Hh signaling: the
generation of Hh protein and the transduction of the signal in receiving
cells. Abrogation of either aspect has profound consequences for the
developing embryo. Cholesterol is essential for the maturation of Hh.
During biosynthesis, when SHh undergoes the autocatalytic cleavage, a
cholesterol moiety is attached to Hh-N (Porter et al. 1996). The cholesterol modification makes Hh-N lipophilic and appears to tether it to the
cell surface (Bumcrot et al. 1995; Porter et al. 1995). This anchoring
event has important biological implications, as it appears to decrease the
range of action of Hh while increasing Hh concentration at its site of
synthesis. Expression in Drosophila of Hh-N lacking the cholesterol
into right and left hemispheres. As in Shh mutant mice, alobar HPE in
humans is often accompanied by cyclopia, a primitive nasal structure,
and midline clefting. The striking similarity of Shh deficient mice to
human HPE quickly led to the identification of SHH mutations in both
familial and sporadic HPE (Roessler et al. 1996).
The majority of SHH mutations in HPE patients result in amino acid
substitutions rather than premature stop codons (Roessler et al. 1996;
Roessler et al. 1997). These mutations are predicted to reduce SHH
function, in part by affecting a critical aspect of its biosynthesis. Normally, Hh proteins are synthesized as precursors that are cleaved by an
autocatalytic reaction into N-terminal (Hh-N) and C-terminal fragments
(Hh-C) (Lee et al. 1994; Bumcrot et al. 1995; Valentini et al. 1997). All
of the signaling activity appears to reside in the highly conserved Hh-N
(Porter et al. 1995). Hh-C, while devoid of signaling activity, possesses
an enzymatic activity that is responsible for Hh self-cleavage (Lee et al.
1994; Porter et al. 1995). At least half of the HPE mutations occur in
SHH-C and may prevent SHH from undergoing the cleavage reaction
(Roessler et al. 1997). This is consistent with work in Drosophila where
mutations in Hh-C impair Hh maturation and function (Porter et al.
1995). Recent evidence implicating cholesterol in Hh signaling sheds
further light on the nature of these mutations.
12.5 The Role of Cholesterol in Hh Signaling
12.5.1 Attachment of Cholesterol to Hh
Cholesterol is important in two distinct aspects of Hh signaling: the
generation of Hh protein and the transduction of the signal in receiving
cells. Abrogation of either aspect has profound consequences for the
developing embryo. Cholesterol is essential for the maturation of Hh.
During biosynthesis, when SHh undergoes the autocatalytic cleavage, a
cholesterol moiety is attached to Hh-N (Porter et al. 1996). The cholesterol modification makes Hh-N lipophilic and appears to tether it to the
cell surface (Bumcrot et al. 1995; Porter et al. 1995). This anchoring
event has important biological implications, as it appears to decrease the
range of action of Hh while increasing Hh concentration at its site of
synthesis. Expression in Drosophila of Hh-N lacking the cholesterol