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Genes Dev. Jan 1, 2006; 20(1): 22–27.
PMCID: PMC1356097

Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition

Abstract

We report the identification of a novel protein that participates in Hedgehog-mediated patterning of the neural tube. This protein, named Tectonic, is the founding member of a previously undescribed family of evolutionarily conserved secreted and transmembrane proteins. During neural tube development, mouse Tectonic is required for formation of the most ventral cell types and for full Hedgehog (Hh) pathway activation. Epistasis analyses reveal that Tectonic modulates Hh signal transduction downstream of Smoothened (Smo) and Rab23. Interestingly, characterization of Tectonic Shh and Tectonic Smo double mutants indicates that Tectonic plays an additional role in repressing Hh pathway activity.

Keywords: Shh, signal transduction, mouse development, neural patterning, open brain

Hh signals are secreted proteins essential for normal development and tissue homeostasis. Misregulation of Hh signaling in humans can lead to congenital defects and cancers (McMahon et al. 2003). The most extensively studied function of the Hedgehog (Hh) family member Sonic hedgehog (Shh) is its role in the developing neural tube. There, Shh acts as a morphogen to direct the production of particular neuronal subtypes at defined dorsoventral positions (Jacob and Briscoe 2003). Shh mediates its effects by binding to its receptor, Patched (Ptch). Ptch, in the absence of Shh, represses the downstream signaling pathway by inhibiting the activity of Smoothened (Smo), a seven-transmembrane protein. Binding of Shh to Ptch relieves the repression of Smo, triggering events that culminate in the activation of transcription factors of the Gli family. How Hh signals are transduced is incompletely understood.

Results and Discussion

Through a screen for genes encoding secreted and transmembrane proteins (Skarnes et al. 1995; Mitchell et al. 2001), we identified a novel gene which, because it is involved in a diverse range of developmental processes, we named Tectonic after the Greek word for builder. Conceptual translation of Tectonic indicates that it encodes a 63-kDa protein with no recognized domains other than an N-terminal signal peptide. Genomic database searches identify two other mammalian Tectonic family members, Tect2 and Tect3, which are 49% and 58% similar to Tectonic, respectively (Supplementary Fig. 1). The Drosophila genome contains a single Tectonic homolog. Thus, Tectonic is the founding member of an evolutionarily conserved family of proteins of undetermined function.

To assess whether Tectonic is secreted as predicted, we created a fusion between the putative Tectonic signal peptide and alkaline phosphatase. This fusion is robustly secreted by Cos7 cells, indicating that the signal peptide is functional (Supplementary Fig. 2). Interestingly, full-length Tectonic is not secreted by Cos7 cells, suggesting that its secretion may be regulated.

Insertion of the gene trap vector in Tectonic occurs in the first of 12 introns (Fig. 1A). The resultant mutant allele encodes a fusion between the first 57 amino acids of Tectonic and a membrane-spanning βgeo reporter (Mitchell et al. 2001). Given that no wild-type transcript is detectable in Tectonic mutants by RT–PCR and Northern blot analyses (Fig. 1B,C), and that transmembrane βgeo fusion proteins are retained in intracellular compartments (Skarnes et al. 1995), the Tectonic gene trap is likely to be a null allele.

Figure 1.
Tectonic is expressed in domains of Hh signaling, and is essential for embryonic development. (A) The mouse Tectonic gene is comprised of 13 exons on chromosome 5. The gene trap consists of a strong splice acceptor (SA) followed by an ORF encoding a transmembrane ...

During embryonic development, Tectonic is expressed in regions that participate in Hh signaling. Tectonic is first expressed during gastrulation stages in the ventral node (Fig. 1D,E). At embryonic day 9.5 (E9.5), Tectonic is expressed in the gut endoderm, limb buds, notochord, somites, neural tube and floorplate (Fig. 1F). Unlike regulators of Hh signaling such as Ptch and Hhip (Goodrich et al. 1996; Marigo and Tabin 1996; Chuang and McMahon 1999), Tectonic is not a transcriptional target of Hh signaling (Supplementary Fig. 3B,C).

Tectonic mutants die between E13.5 and E16.5 and display holoprosencephaly (Fig. 1G), a defect associated with reduced Hh signaling (Chiang et al. 1996). Shh mediates induction of the floorplate, a histologically distinct cell population at the ventral midline of the neural tube. Like Shh mutants and Gli2 mutants (Chiang et al. 1996; Ding et al. 1998; Matise et al. 1998), Tectonic mutants fail to form floorplates and, instead, cells of neural morphology are present at the midline (Fig. 2A). Molecular analysis with the markers Shh and FoxA2 (Hnf3β) confirms that Tectonic is required for floorplate formation (Figs. (Figs.2B,2B, ,3B).3B). However, the notochord forms normally in Tectonic mutants as judged by Shh and Brachyury expression (Fig. 2B; Supplementary Fig. 3D). Thus, axial defects in Tectonic mutants are confined to the floorplate.

Figure 2.
Tectonic is required for Hh-mediated patterning of the ventral neural tube. (A) Hematoxylin-and-eosin-stained transverse sections of E9.5 embryos. Tectonic mutants lack a histologically distinct floorplate (arrow). (BH) In situ hybridization ...
Figure 3.
Tectonic is epistatic to Ptch and Rab23. (A) Lateral views of E9.5 littermates. Ptch mutants display a characteristic open neural tube and defective turning whereas normal turning is largely restored in Tectonic Ptch double mutants. (BD) Transverse ...

In addition to the floorplate, high levels of Hh signaling are required for the induction of the adjoining V3 interneurons (Litingtung and Chiang 2000; Wijgerde et al. 2002). Analysis of neural tube patterning reveals that, like Shh, Tectonic is required for formation of the Sim1-expressing V3 interneurons (Fig. 2C). Nkx2.2, a marker of the progenitors of the V3 interneurons (Briscoe et al. 1999), is also lost in Tectonic mutants (Fig. 3C), suggesting that these defects are not due to defects in neuronal maturation, but in their specification. Moreover, the Tectonic-dependent defects in ventral neural development are not limited to the V3 interneurons. Tectonic mutants also display a variable reduction in the number of Islet1/2-positive motor neurons (Fig. 3D). However, Tectonic is not required for the expression of Dbx1 or Dbx2 (Fig. 2D; data not shown), indicating that Tectonic function is not essential for the development of more dorsal cell fates within the neural tube.

The loss of ventral neural markers in Tectonic mutants is accompanied by a ventral expansion of genes normally restricted to more dorsal domains. High levels of Hh signaling exclude expression of Irx3 from the V3 and motor neuron progenitor (p3 and pMN) domains (Briscoe et al. 2000). In Tectonic mutants, Irx3 expression expands to include all but a small number of ventral cells (Fig. 2E). Similarly, expression of Pax6, another factor repressed by high Hh signaling (Ericson et al. 1997), is dramatically expanded in Tectonic mutants (Fig. 3B). Taken together, these changes in marker expression indicate that Tectonic is essential for the induction of the ventral-most cell types of the neural tube. These patterning defects are qualitatively similar to those caused by mutations in Shh or Gli2 (Chiang et al. 1996; Ding et al. 1998; Matise et al. 1998; Litingtung and Chiang 2000), suggesting that Tectonic participates in Hh signaling.

To test this hypothesis, we examined the expression of Gli1 and Ptch, two general Hh transcriptional targets. Significantly, Gli1 expression is reduced throughout Tectonic mutant embryos at E9.5 (Fig. 2F). In the developing neural tube of Tectonic mutants, expression of Gli1 and Ptch is similarly dramatically reduced (Fig. 2G,H). Hh signaling in the neural tube is antagonized by Bmp activity (Barth et al. 1999; Kawakami et al. 2005). Expression of Msx1, a readout of Bmp pathway activity in the dorsal neural tube (Liu et al. 2004), is normal in Tectonic mutants (Supplementary Fig. 4), suggesting that Tectonic does not influence Hh signaling indirectly by altering Bmp activity. Together, these results argue that Tectonic acts in neural patterning by positively regulating the Hh pathway.

Conceptually, Tectonic could contribute to Hh signaling by participating in the creation of the Hh protein gradient or in the interpretation of that gradient. To distinguish between these two possibilities, we carried out epistasis experiments with Ptch mutants. If Tectonic acts in Hh processing, release or distribution, Ptch should be epistatic to Tectonic. However, if Tectonic acts in Hh signal transduction, Tectonic should be epistatic to Ptch. Ptch-dependent defects in embryonic turning and dorsal neural tube closure are ameliorated in Tectonic Ptch double mutants (Fig. 3A). Embryos lacking Ptch function show marked expansion of the ventral domains of the neural tube (Fig. 3B–D; Goodrich et al. 1997). Examination of the dorsoventral patterning of the neural tube of Tectonic Ptch double mutants reveals a loss of ventral neural fates indistinguishable from those of Tectonic single mutants (Fig. 3B–D).

Like Ptch, Rab23 is a negative regulator of the Hh pathway (Eggenschwiler et al. 2001; Huangfu et al. 2003). Embryos homozygous for the opb2 mutation in Rab23 display a ventralized neural tube (Fig. 3E,F; Eggenschwiler and Anderson 2000). As with Ptch, embryos mutant for both Rab23 and Tectonic display neural tube patterning defects identical to those of Tectonic single mutants (Fig. 3E,F). Together, these results indicate that Tectonic is epistatic to both Ptch and Rab23. As Rab23 has been reported to act downstream of Smo (Huangfu et al. 2003), these data suggest that Tectonic modulates Hh transduction at a point downstream of Ptch, Smo, and Rab23.

To investigate whether the Tectonic-mediated effects on neural tube patterning reflect changes in Hh pathway activity, we assayed the expression of Gli1 in Tectonic Ptch double mutants (Fig. 3G). Loss of Ptch function causes ectopic expression of high levels of Gli1 in the dorsal neural tube. In contrast, Tectonic Ptch double mutants display uniform low levels of Gli1 expression (Fig. 3G). These data confirm that Tectonic is essential for maximal activation of the Hh pathway. Furthermore, our results strongly suggest that Tectonic functions downstream of both Ptch and Rab23 in the Hh signal transduction pathway, and not in Hh production or release. Consistent with this conclusion, Shh protein is distributed in a dorsoventral gradient in Tectonic mutant neural tubes similar to that of wild-type neural tubes (Supplementary Fig. 5).

One of the most prominent defects displayed by Shh mutants is the severe reduction in forebrain development (Chiang et al. 1996). Strikingly, Tectonic Shh and Tectonic Smo double mutants have considerably larger forebrains than do either Shh or Smo mutants (Fig. 4A; Supplementary Fig. 6). Although these results appear paradoxical given the reduced forebrains of Tectonic mutants, they suggest that there is a higher level of Hh activity in double mutants than in single mutants, implying that in addition to its role in pathway activation, Tectonic exerts a repressive effect on the pathway. To test whether this is the case, we examined neural tube expression of Dbx1 and Dbx2, markers of the p0 and p1 precursors that are induced by low Hh levels (Wijgerde et al. 2002). If p0 and p1 formation in Tectonic mutants requires Shh activity, Tectonic Shh double mutants should show a reduction in Dbx1 and Dbx2 expression similar to that displayed by Shh mutants. However, our analysis reveals a dramatic increase in Dbx1- and Dbx2-expressing cells in Tectonic Shh double mutants as compared to Shh single mutants (Fig. 4B,C). These surprising results demonstrate that Dbx1 and Dbx2 expression in Tectonic mutants is independent of Shh, and suggest that Hh pathway activity is higher in Tectonic Shh double mutants than in Shh mutants.

Figure 4.
In addition to its role in mediating high levels of Hh signaling, Tectonic functions to repress low levels of Hh pathway activation. (A) Lateral view of E10.5 embryos. Shh mutants are one-third the size of littermates and show severely diminished forebrains. ...

To assess whether increased Dbx1 and Dbx2 expression reflects increased Hh pathway activation, we examined Ptch expression in Tectonic Shh double mutants. We found that the abrogation of Ptch expression exhibited by Shh mutants is indeed partially alleviated by loss of Tectonic function (Fig. 4D), indicating that levels of Hh pathway activation are in fact higher in Tectonic Shh double mutants than in Shh mutants. The genetic interaction between Shh and Tectonic is similar to that observed between Shh and Gli3 (Litingtung and Chiang 2000) and suggest that Tectonic acts in a Shh-independent fashion to repress the Hh pathway. Taken with the forebrain data, these results reveal that Tectonic plays dual essential roles in both activating and inhibiting the Hh pathway in the anterior and posterior neural tube.

The loss of the activator function can be depicted as a rightward shift in the Hh pathway activity gradient of Tectonic mutants (Fig. 4E). Our additional finding that Tectonic inhibits Hh pathway activation in the absence of Shh can be represented graphically as a leftward shift in the Hh pathway activity gradient of Tectonic Shh double mutants relative to Shh mutants (Fig. 4E). This evidence that Tectonic functions in Hh signal transduction to fully activate the pathway in the presence of high Hh levels and to repress the pathway in the absence of Hh signals may reflect a combination of decreased function of both Gli activators and Gli repressors. In this regard, Tectonic joins a number of recently described regulators of Hh signal transduction including mouse IFT proteins (Huangfu et al. 2003; Liu et al. 2005) and zebrafish Iguana (Sekimizu et al. 2004; Wolff et al. 2004). Additionally, a Drosophila protein complex that includes Cos2 is similarly required for full pathway activation (Robbins et al. 1997; Sisson et al. 1997; Wang and Holmgren 2000; Wang et al. 2000; Lefers et al. 2001) and inhibition (Methot and Basler 2000; Stegman et al. 2000; Wang et al. 2000; Lefers et al. 2001). Tectonic is the first extracytosolic factor shown to act in this dual capacity.

Although the molecular mechanism by which Tectonic functions is not clear, our double mutant analyses suggest that it modulates Hh signal transduction at a point fairly downstream in the pathway. As Rab23 acts in the same region of the pathway and is thought to control vesicle transport, it will be interesting to assess whether it regulates the trafficking of Tectonic.

Materials and methods

Mouse strains

The mouse embryonic stem cell line KST296 carrying an insertion of the pGT1pfs secretory trap vector in the Tectonic gene was isolated as described in Mitchell et al. (2001). Tectonic F1 heterozygotes were backcrossed to C57Bl/6 mice for six generations prior to intercrossing. Genotyping of Tectonic was performed using genomic PCR with a pair of wild-type-specific primers (5′-CGCCTCTTTAGCCCTCTGTT-3′ and 5′-AGAACCTCCACGAGAGCAGA-3′) and a mutant-allele-specific primer (5′-TCTAGGACAAGAGGGCGAGA-3′). Ptch, Rab23, Shh, and Smo embryos were genotyped as described (Chiang et al. 1996; Goodrich et al. 1997; Eggenschwiler et al. 2001; Zhang et al. 2001).

Secretion assays

Cos7 cells were transfected using Fugene6 (Roche) with APTag5 (Gen-Hunter) or APTag5-TectSignal, a vector in which the SEAP signal sequence has been replaced with that of Tectonic. Alkaline phosphatase activity in the supernatant was chemiluminescently measured using the Phospha-Light Assay (Applied Biosystems) and a 20/20n luminometer (Turner BioSystems).

RT–PCR and Northern blot analyses

RT–PCR was performed using exon-spanning primers complementary to Tectonic cDNA 3′ to the gene trap insertion (5′-AATCCGCTGTTCC TTCCAC-3′ and 5′-TGCGTCAGTGTGTGATTCAG-3′), to the βGEO transcript (5′-CTTGGGTGGAGAGGCTATTC-3′ and 5′-AGGTGAG ATGACAGGAGATC-3′), and to G3PD (5′-GTGTTCCTACCCCCAAT GTG-3′ and 5′-TGTGAGGGAGATGCTCAGTG-3′). Northern blots were hybridized to a Tectonic cDNA probe spanning exons 2–12 and a probe to βgeo.

Immunohistochemistry and in situ hybridization

X-gal staining, in situ hybridization, and immunohistochemical staining were carried out using antibodies and protocols as previously described (Ericson et al. 1997; Briscoe et al. 1999, 2000; Takebayashi et al. 2000; Gritli-Linde et al. 2001) with the exception of rabbit α-Pax6 antibody (Covance Research Products), which was used at 1:300. The α-FoxA2, α-Nkx2.2, α-Islet1/2, α-Msx1/2, and α-Pax3 antibodies were obtained from the Developmental Studies Hybridoma Bank maintained by the University of Iowa under contract NO1-HD-7-3263 from the NICHD.

Gene analysis and accession numbers

Sequences of Tectonic family members were aligned using ClustalW and Boxshade 3.21. Domain analysis was performed with SignalP 3.0 and HMMTOP 2.0. Mouse Tectonic cDNA sequence, GenBank accession number DQ278867; human Tectonic cDNA sequence, GenBank accession number DQ278868; mouse Tect2 cDNA sequence, GenBank accession number DQ278869; human Tect2 cDNA sequence, GenBank accession number DQ278870; mouse Tect3 cDNA sequence, GenBank accession number DQ278871; human Tect3 cDNA sequence, GenBank accession number DQ278872; Drosophila dTectonic cDNA sequence, GenBank accession number DQ278873.

Acknowledgments

We are grateful to Debbie Pangilinan for expert mouse husbandry, to Andrew Norman for technical assistance, and to Pao-Tien Chuang and Andrew McMahon for the anti-Shh antibody Ab80. We thank Kevin Mitchell, Chulho Kang, and Marc Tessier-Lavigne for help generating the KST296 ES cell line and the Tectonic mice. This work was assisted by valuable conversations with Gail Martin, Pao-Tien Chuang, Didier Stainier, and Tom Kornberg. This research was supported by funding from the Chicago Community Trust and grants from the NICHD and NIMH. J.R. is a UCSF Fellow generously supported by the Sandler Foundation and a March of Dimes Basil O'Connor Award.

Notes

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1363606.

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