QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online December 8, 2005
doi: 10.1242/10.1242/dev.02169

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huangfu, D. Articles by Anderson, K. V. Search for Related Content PubMed PubMed Citation Articles by Huangfu, D. Articles by Anderson, K. V.

Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates

Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA

View larger version (31K): [in a new window]   Fig. 1. The Hedgehog pathway in Drosophila and vertebrates. The Hedgehog (Hh) pathway in Drosophila (A,B) and in vertebrates (C,D) in the absence (A,C) or presence (B,D) of the Hh ligand. (A) In the absence of Hh, Ptc prevents the cell-surface localization of Smo, and Ci forms a complex with Cos2, Fu and Sufu, which targets Ci for proteolytic processing into the repressor form (CiR). (B) In the presence of high levels of Hh ligand, Ptc inhibition is relieved; Smo accumulates at the plasma membrane and forms a complex with Cos2 and Fu through its C-terminal tail; Ci is activated. (C) In the absence of Hh, Ptch1 prevents the accumulation of Smo in cilia, possibly through the action of a small molecule. Gli3 is processed into a repressor form (Gli3R) in a cilia-dependent manner. The activation of all Gli proteins is inhibited by Sufu, Iguana (for zebrafish) and probably Cos2. (D) In the presence of high levels of Hh ligand, Ptch1 inhibition is relieved; Smo is targeted to cilia and activates Gli proteins in a cilia-dependent manner. Gli3 processing is also inhibited. p, phosphorylation; PKA, protein kinase A.

View larger version (30K): [in a new window]   Fig. 2. Neural tube phenotypes in mouse Hh pathway mutants. (A) In the wild-type E10.5 embryo, roof-plate cells are specified at the dorsal (D) midline (dark blue), and dorsal neural progenitors express Pax3 and Pax7 (blue). Six ventral (V) neural cell types are specified, each marked in a different color (Jacob and Briscoe, 2003). (B) In E10.5 Shh mutants, ventral neural cell types are absent, V0 and V1 interneurons are present at the ventral midline, and dorsal progenitor markers are expressed throughout the neural tube (Chiang et al., 1996; Wijgerde et al., 2002). (C) Smo is required cell autonomously for specification of floor plate, V3, motoneurons (MNs) and V2 cells; for restriction of dorsal fates; and for the correct positioning of V1 and V0 interneurons (Wijgerde et al., 2002). (D) Gli2 mutants lack floor-plate cells and have reduced number of V3 cells (Ding et al., 1998; Matise et al., 1998). (E) V2, V1 and V0 interneurons are expanded dorsally in Gli3 mutants (Persson et al., 2002). (F) Gli2/Gli3 double mutants lack both floor-plate cells and V3 interneurons (Bai et al., 2004; Lei et al., 2004; Motoyama et al., 2003). (G) IFT mutants (Ift172, Polaris and Dnchc2) lack floor-plate cells, V3 interneurons and nearly all MNs; V2, V1 and V0 cells are expanded ventrally (Huangfu and Anderson, 2005; Huangfu et al., 2003; Liu et al., 2005). (H) Ptch1 mutants have a ventralized neural tube (Goodrich et al., 1997; Motoyama et al., 2003). No roof-plate or dorsal progenitor cells are specified, and ventral cell types are expanded dorsally. (I) Rab23 mutants have a ventralized caudal neural tube (Eggenschwiler et al., 2005; Eggenschwiler et al., 2001). No roof-plate or dorsal progenitor cells are specified, and ventral cell types are expanded dorsally. (J) Fkbp8 mutants have a ventralized caudal neural tube (Bulgakov et al., 2004). No roof-plate cells are present; ventral cell types are expanded more dorsally than in Rab23 mutants. Unlike in Rab23 mutant, dorsal progenitor cells are present.

View larger version (29K): [in a new window]   Fig. 3. Alignment of the fly Smo protein with the zebrafish/mouse Smo. The transmembrane (TM) domain and the N-terminal regions of the protein are relatively conserved from fly to mammals. The cysteine-rich domains (CRDs) in fish and mouse smoothened (Smo) are very similar (70% identical, 82% similar), while the CRD in fly Smo is more divergent (43% identical, 56% similar between fly and mouse). C-terminal to the 180 residues adjacent to the 7th TM domain of Drosophila Smo, there are only short patches of homology between Drosophila Smo and either the zebrafish or the mouse Smo, whereas this region is relatively conserved (31% identity) between zebrafish and mouse Smo. This same region in flies is important for binding to Cos2, indicating that the interaction between Smo and Cos2 is not conserved in vertebrates. The protein kinase A phosphorylation sites in the fly Smo protein are not conserved. PKA, protein kinase A.

View larger version (14K): [in a new window]   Fig. 4. The regulation of Ci/Gli proteins. The full-length Ci protein (gray) can be proteolytically cleaved to generate a repressor form (blue) or activated to generate an activator form (red). The vertebrate Gli homologs share similar domain structures with Ci, but only Gli3 is known to be cleaved into a functional repressor form. The conserved and diverged aspects of the regulation of Ci/Gli activation and cleavage are shown. The zinc-finger domains are indicated by stripes. Components that have been shown either to promote or to prevent these processes are indicated in the figure. Components shown in black are common to both vertebrates and invertebrates; those in yellow are likely to be conserved, but there is insufficient in vivo data to support their conserved roles; those in purple can play a role in invertebrates; and those in green function in mouse and zebrafish, but not in fly. CKI, casein kinase 1; GSK3ß, glycogen synthase kinase 3ß; PKA, protein kinase A.