The Hedgehog family of proteins are signaling proteins that are crucial for a number of physiological
processes including morphogenesis during development. In adult organisms, it is also involved in the
regulation of theca cell development in growing follicles (1) and in regulating the development and
function of the somatic cells of the testis (2;3).Vertebrates are known to have 3 Hedgehog genes, which
show different spatio-temporal expression patterns and perform specialized functions. These are -
Desert hedgehog (Dhh), Indian hedgehog (Ihh), and Sonic hedgehog (Shh). The Patched (PTCH) proteins
(Patched 1 and Patched 2 - PTCH1 and PTCH2) serve as receptors for the Hedgehog proteins.
In the 'off' state, PTCH receptors inhibit the Smo protein by mechanism(s) which are still not understood
completely. In this state, the Gli2/3 Zn-finger transcription factors are phosphorylated and processed in
a proteasome-dependent manner to generate a transcriptionally repressor form. SUFU, a cytoplasmic
protein, was also found to interact with all the three Gli proteins resulting in the repression of its
transcriptional activity (4, 5).
In the 'Signaling cell', which is the cell which secretes the Hedgehog proteins, an active ligand
is produced following processing of the precursor Hedgehog protein. This processing involves
autocleavage by the catalytic domain and bi-lipidation (cholesterol moiety at C-terminus and palmitate
at the N-terminus) of the Hedgehog protein (6). These active ligands travel to the 'responding cell'
via interactions with glypicans and megalin. On the responding cell, the active ligand interacts with
PATCHED 1 (PTCH1) and PATCHED 2 (PTCH2), which results in the activation and translocation of
Smoothed (Smo) to the cilium(plasma membrane in Drosophila). Activation of Smo results in the
inhibition of Gli proteolysis and the production of the transcriptional repressor form. This might
also promote the formation of the transcription activator form of the protein. The G-protein
coupled receptor kinase-2 enhances the association between beta-arrestin 2 and Smo probably by
phosphorylating Smo. The two proteins also mediates increased internalization of Smo in a clathrin-
dependent process and increased Hedgehog signaling (7,8). Kif7, a Drosophila Costal2 (Cos2) homolog,
is capable of interacting with the Gli proteins and is known to exert positive and negative effects on
Hedgehog signaling (9,10,11). The Fused (Fu) homolog, which can form a complex with Kif7, Gli and
and SuFu (similar to Drosophila Gli, Cos2, Su and SuFu) may also be involved in the regulation of this
1) Wijgerde M, Ooms M, Hoogerbrugge JW, Grootegoed JA (2005) Hedgehog Signaling in Mouse
Ovary: Indian Hedgehog and Desert Hedgehog from Granulosa Cells Induce Target Gene Expression in
Developing Theca Cells. Endocrinology, 146:3558-66.
2) Bitgood MJ, Shen L, McMahon AP(1996) Sertoli cell signaling by Desert hedgehog regulates the male
germ line. Curr Biol, 6:298-304.
3) Yao HH, Whoriskey W, Capel B (2002) Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell
fate in testis organogenesis. Genes Dev, 16:1433-40.
4) Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de
Sauvage FJ, Rosenthal A (1999) Characterization of the human suppressor of fused, a negative regulator
of the zinc-finger transcription factor Gli. J Cell Sci, 112 :4437-48.
5) Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftgård R, Liu A (2009) Suppressor of Fused inhibits
mammalian Hedgehog signaling in the absence of cilia. Dev Bio, 330:452-60
6) Cohen MM Jr (2010) Hedgehog signaling update. Am J Med Genet A , 152A:1875-914
7) Meloni AR, Fralish GB, Kelly P, Salahpour A ,Chen J K, Wechsler-Reya RJ, Lefkowitz RJ, Caron MG
(2006) Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell
8) Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ (2004) Activity-
dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science, 306:2257-60.
9) Liem KF Jr, He M, Ocbina PJ, Anderson KV (2009) Mouse Kif7/Costal2 is a cilia-associated protein that
regulates Sonic hedgehog signaling. Proc Natl Acad Sci USA, 106:13377-82.
10)Cheung HO, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, Law KK, Briscoe J, Hui CC (2009) The
kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling.
Sci Signal, 2:ra29.
11)Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales
SJ, Solloway MJ, de Sauvage FJ, Peterson AS (2009) The mammalian Cos2 homolog Kif7 plays an essential
role in modulating Hh signal transduction during development. Curr Biol, 19:1320-6.
12)Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ
(2000) Gli regulation by the opposing activities of fused and suppressor of fused. Nat Cell Biol, 2:310-2.