1,594

Hedgehog Signaling in Palatal and Facial Development

Alan Nguyen, Dalton Pham, Vi Nguyen, Greg Choon Chung, Benjamin Levi, Aaron W. James, Michelle A. Scott

Alan Nguyen, Dalton Pham, Vi Nguyen, Aaron W. James, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, the United States
Alan Nguyen, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, the United States
Greg Choon Chung, Division of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, the United States
Benjamin Levi, University of Michigan, Plastic Surgery, Department of Surgery, Ann Arbor, MI, the United States
Michelle A. Scott, Nationwide Children’s Hospital, Columbus, OH, the United States

Correspondence to: Michelle A. Scott, DDS, MBA, Department of Plastic Surgery, Nationwide Children’s Hospital, 700 Children’s Drive A2530, Columbus, OH 43205, the United States
Email: Michellescott123@yahoo.com
Telephone: +1-310-206-6754
Fax: +1-310-267-2058
Received: July 12, 2015
Revised: August 1, 2015
Accepted: August 3, 2015
Published online: October 23, 2015

ABSTRACT

The Hedgehog (HH) signaling pathway has shown to be crucial in modulating mammalian skeletal and craniofacial development, mutations in which can lead to craniofacial malformations such as cleft lip/palate. With three known homologues, including Desert Hedgehog (DHH), Sonic Hedgehog (SHH), and Indian Hedgehog (IHH), only the latter two are expressed in the craniofacial complex. The focus of this review pertains to the role of SHH and IHH signaling in palatal and facial bone development, and the underlying differences between the two. While expression of both SHH and IHH is required for calvarial ossification and craniofacial development, they differ in where they are expressed and how they elicit their effects. SHH is not expressed in the facial mesenchyme, but rather in the frontonasal and maxillary cranial suture mesenchyme. IHH expression by contrast occurs on developing palatine bone and in most studies pertains to endochondral ossification, playing a key role in inducing cell proliferation and differentiation.

Key Words: Facial development; Palatal development; Sonic Hedgehog; Indian Hedgehog

© 2015 The Authors. Published by ACT Publishing Group Ltd.

Nguyen A, Pham D, Nguyen V, Chung GC, Levi B, James AW, Scott MA. Hedgehog Signaling in Palatal and Facial Development. International Journal of Orthopaedics 2015; 2(5): 385-390 Available from: URL: http://www.ghrnet.org/index.php/ijo/article/view/12794

Introduction

The Hedgehog (HH) signaling pathway is responsible for regulating the morphogenesis and development of many organs, including skeletal development in mammalian vertebrate organisms[1]. With three known homologues of the HH ligand, consisting of Desert Hedgehog (DHH), Sonic Hedgehog (SHH), and Indian Hedgehog (IHH), only the latter two are critical to embryonic skeletal development; knockout in murine models results in neonatal lethality and multiple craniofacial abnormalities such as holoprosencephaly and cleft lip/palate[2-7]. Despite remaining well conserved across their signaling cascades, the HH ligands have distinct domains of expression and function, which at times may overlap[8].

The SHH signaling pathway is critical to embryonic development and is thought to depend upon epithelial-mesenchymal interactions[9]. SHH plays a distinct role in determining the organizational pattern of neural tubes, somites, and limbs[9], is implicated in vertebrate organogenesis, and promotes adult stem cell proliferation in hematopoietic, mammary, and neural tissues[10]. SHH regulates osteoprogenitor cell differentiation by enhancing osteogenic differentiation and inhibiting adipogenic differentiation in multiple mesenchymal cell types[11]. Furthermore, SHH is involved in skeletogenesis and development of facial, appendicular, and axial skeletal patterns[9]. Thus, improper ossification occurs in developing animals as a result of impaired SHH signaling and can lead to mutations such as cleft palate[12].

Meanwhile, the IHH signaling pathway is involved in chondrocyte differentiation and proliferation, as well as maturation during endochondral ossification. IHH coordinates endochondral growth and morphogenesis via parathyroid hormone related-protein-dependent and –independent pathways[13]. Furthermore, in the context of palatal development, IHH expression has shown to be specific to the developing palatine bones[14,15].

The focus of this review is to further elucidate how SHH and IHH elicit their effects on palatal and facial development, and the differences between the two in this context. While both also play a major role in fusion of cranial sutures and calvarial ossification, this is beyond the scope of this review (Please see[16] for a detailed review on HH signaling in cranial suture fusion).

Brief Review of the Hedgehog Signaling Mechanism

The HH signaling pathway plays an essential role in mesodermal tissue patterning and differentiation[17,18]. Originally identified in Drosophila melanogaster as an embryonic segment polarity gene[19], HH was later isolated in vertebrate organisms as a modulator of mammalian skeletal development[1]. Three homologues of the HH family include DHH, SHH, and IHH[8]. Though DHH is implicated in Leydig cell differentiation in the male reproductive system and Schwann cell function, its function is not well-studied in the context of bone biology[20-22]. Conversely, both SHH and IHH are critical to embryonic skeletal development. Knockout studies using murine models have resulted in neonatal lethality and multiple craniofacial abnormalities such as holoprosencephaly[2-7]. In addition, SHH regulates vertebrate organogenesis and promotes adult stem cell proliferation in hematopoietic, mammary, and neural tissues[23,24], whereas IHH couples chondrogenesis to osteogenesis during endochondral bone formation primarily in the appendicular skeleton[25].

The HH signaling pathway occurs via a three-step mechanism which is generally conserved across all three homologues[26]. First, activation of the pathway occurs via autocatalytic cleavage, followed by modification of the C and N-termini with cholesterol and palmitoyl acid respectively[27-29]. Hedgehog acyltransferase (HHAT) is essential to the post-translational palmitoylation of HH, and HH secretion is downregulated in the absence of this enzyme[11]. The conversion of HH to a multimeric form is critical to increasing its membrane solubility and ability to undergo paracrine signaling[26]. Next, the activated HH is then released via Dispatched (DISP), a 12-pass transmembrane protein from the signaling cell, thus enabling it to bind to its receptor Patched (PTCH) on the receiving cell[30]. This binding disinhibits and releases Smoothened (SMO), a 7-pass transmembrane protein that activates downstream target genes through interaction with transcription factors from the glioblastoma gene product family (Gli)[31]. Consequently, HH-Gli signaling modulates lineage commitment and cell fate during differentiation primarily through transcription[32].

>Hedgehog Signaling in Palatal Development

The primary palate comprises all structures anterior to the incisive foramen including the lip, nostril sill, alveolus and hard palate anterior to the incisive foramen. The medial and lateral nasal prominences of the frontonasal process migrate and fuse with the maxillary prominence to form the primary palate in humans during weeks 4-7 of gestation. The secondary palate includes the hard palate posterior to the incisive foramen as well as the entire soft palate. Migration and fusion of the lateral palatal process of the maxillary prominence form the secondary palate between 5-12 weeks of gestation in humans. At 8 weeks of gestation the lateral palatal processes are vertical and as the tongue drops, the palatal processes rotate into a horizontal position and fuse from anterior to posterior. The right lateral palatal process becomes horizontal before the left explaining the greater incidence of deformities on the left side. The cause of aberrations in these developmental processes are still not completely understood and recent studies have explored the role of HH signaling in cleft palatal deformities. HH signaling has been shown to play a crucial role in skeletogenesis, and is specifically implicated in palatal development[33-35]. For example, Morava et al examined a case study of a 14-month-old girl with submucous cleft palate and found a duplication of the chromosome region 7q35-qter located near the SHH gene on 7q36, suggesting that HH regulates palatogenesis[6]. Several studies have also investigated how the HH signaling pathway affects cranial neural crest cells (CNCC), which serve as the progenitors of palatal bones. Jeong et al found that deletion of Smo in murine embryonic CNCC results in craniofacial abnormalities such as an incomplete nasal septum, absent vomer and hyperplasia[36]. Furthermore, SHH rescues CNNC from ethanol-induced cell death and the associated craniofacial growth defect[37]. Thus, these early studies suggest that HH signaling plays a role in palatogenesis, likely through affecting the osteoprogenitor cells.

Although both SHH and IHH homologues play a significant role in palatal development, it is primarily SHH that regulates palatal growth. Rice et al. showed that prior to palatal shelf elevation, SHH signaling regulates the growth and morphogenesis of the palatal shelves and is limited to thickened palatal oral epithelium[14]. After palatal shelf elevation, SHH is strongly expressed in the oral epithelium in a pattern of stripes that correspond to the future rugae palatine[14,33]. SHH is also an important epithelial signal for regulating palatal growth, which is dependent upon reciprocal interactions between the oral ectoderm and underlying neural-crest-derived mesenchyme[34]. Specifically, SHH-Smo signaling modulates the expression of transcription factors Foxf1a, Foxf2, and Osr2, and Bmp2, Bmp4, and Fgf10, which are present in the palatal mesenchyme and affect palatal epithelial cell proliferation[34]. Moreover, mice lacking SHH signaling develop secondary cleft palate[33].

In another study, Sasaki et al implicated the involvement of Shh and Pax9 in transforming growth factor-beta (TGF-β3)-regulated normal palatal fusion by investigating the expression of both genes during normal mouse palate development and in the developing cleft palates of TGF-β3 null embryos 38. Mice lacking TGF-β3 exhibit incomplete failure of palatal shelf fusion and thus are a suitable model to examine the molecular cause of isolated cleft palate[39]. Compared to wild-type mice, Pax9 expression was reduced in the palatal medial edge at the critical time of palatal fusion (embryonic days 14.5-15.5), and Shh expression was reduced throughout embryonic days 12.5-15.5 in the palates of TGF-β3 null mice[38]. Thus, this experiment indicates that the correlation between the expression of TGF-β3, Pax9, and Shh is crucial for normal cleft palate formation.

Similarly, Zhang et al used the Msx1-deficient mice model to study the genetic regulation of mammalian palatogenesis through the SHH signaling pathway[40]. Msx1-deficient mice exhibit severe craniofacial abnormalities including cleft secondary palate, an absence of alveolar processes, and arrest of tooth development at the bud stage[41]. Likewise, mutations in the human MSX1 gene are associated with isolated non-syndromic cleft palate and tooth agenesis[42]. Zhang et al has shown that Msx1 is required for the expression of both Bmp4 and Bmp2 in the palatal mesenchyme and Shh in the medial edge epithelium (MEE)[40]. Furthermore, disruption of Msx1 function impairs cell proliferation in the palatal mesenchyme, which leads to formation of cleft secondary palate[40]. However, ectopic expression of Bmp4 in Msx1 knockout mice restores Bmp2 and Shh expression, rescues the cleft palate phenotype, and recovers normal cell proliferation in the palatal mesenchyme[40]. Thus, Bmp4 functions upstream of Bmp2 and Shh to regulate palate development and is able to bypass the requirement for Msx1[40]. Further in vitro analysis revealed that Shh derived from the MEE activates expression of Bmp2 and stimulates cell proliferation[40]. Thus, this study has elucidated how Msx1 regulates Bmp and Shh signaling, which in turn affects mammalian palatogenesis.

Likewise, correlation has also been observed between IHH and palatal osteogenesis. Levi et al found that HH pathway activity colocalizes with osteogenic gene expression of during palatal development[35]. Specifically, upregulation of HH ligand Ihh and HH targets Ptch1, Gli1, and Gli2 coincided with increased expression of Alkaline Phosphatase and Type I Collagen in the palatal mesenchyme and developing palatine bones[35]. Furthermore, Ihh null mice displayed impaired palatal osteogenesis, as indicated through decreased expression of osteogenic markers Runx2 and Osteocalcin and decreased ossification of the palatine bone compared to wild-type mice[35].

Hedgehog Signaling in Facial Bone Development

Craniofacial development is a delicate developmental processes requiring the control of cell commitment, proliferation, and differentiation. SHH and IHH are expressed in the craniofacial complex and are both integral to the process of calvarial ossification. The frontonasal prominence of the forebrain results in nasal and olfactory placodes that become medial and lateral processes. The mandibular arch bifurcates to form mandibular processes that move toward the midline to form the lower mouth. When the facial process fail to fuse, craniofacial clefts can result.

With regards to the craniomaxillofacial skeleton, SHH mediates the development of mid- and upper-face, frontonasal, and maxillary processes[43]. In many studies, similarities were found between the patterning of SHH and BMP expression during neonatal craniofacial development[44,45] as well as with the transcription factor Muscle Segment Homeobox (MSX)-2, a transcriptional repressor of neural crest-derived cells[46,47-49]. In fact, SHH may increase mesenchymal proliferation via promotion of MSX2, a homeobox gene present in osteoblastic cells, in concert with BMP4 signaling[50]. Interestingly, Chong et al found that when SHH signaling is blocked in the brain but SHH is also applied early to the frontonasal ectodermal zone, the formation of the face and upper jaw is significantly improved. This suggests that the SHH signaling, which mediates brain-to-face interaction, is time-dependent[51].

Various other studies have also demonstrated that SHH signaling is essential for early craniofacial development. Cobourne et al investigated the molecular basis of craniofacial defects seen in nevoid basal cell carcinoma syndrome (NBCCS) using a transgenic mouse model expressing Shh in basal epithelium under Keratin 14-promoter[52]. NBCCS is an autosomal dominant or spontaneous disorder characterized by multiple cutaneous basal cell carcinomas, odontogenic keratocysts, skeletal anomalies, and facial dysmorphology including cleft lip and palate[53,54]. It is caused by a mutation in the PTCH1 gene on chromosome 9q22.3-q31 in humans, which encodes the principle receptor for the Hedgehog signaling pathway[55,56]. The five year survival rate is only approximately 50%[57]. Cobourne et al showed that increased Hedgehog signal transduction in K14-Shh mice influences cell fate within the craniofacial region by affecting the processes of palatogenesis and odontogenesis[52]. Increased Shh activity in the medial edge epithelium of the palate prevents apoptosis and subsequently hinders palatal shelf fusion, whereas high levels of Shh in odontogenic epithelium is associated with lack of cell proliferation and arrested tooth development at the bud stage[52]. Thus, appropriately regulated Hedgehog signaling is crucial towards proper craniofacial development, as hallmarks of NBCCS such as orofacial clefting and hypodontia can both result from increased Shh signaling activity within embryonic epithelial tissues[52].

IHH expression, by contrast, has been fully defined in its function to induce cell proliferation and differentiation, found mainly on the osteogenic fronts of the calvarial bones. This finding is consistent with limb development where IHH plays a greater role at the site of growth plates and cartilage formation and whereas its role in developed osteoblasts is less significant. IHH regulates chondrocyte differentiation and stimulates endochondral bone formation[26]. IHH stimulates the proliferation of chondrocytes at the growth plate and further in development, osteoblast differentiation. In addition, it also regulates chondrocyte hypertrophic differentiation through a negative feedback loop involving IHH-parathyroid hormone-related protein. As well, IHH promotes ossification and fusion of the cranial and palatine bones; IHH expression on the bony interfaces of synostotic rabbits may support the role of IHH in premature suture fusion[58]. Studies have suggested that IHH lies upstream of BMP2/4 signaling and may a part of the regulatory network that controls BMP expression, thereby influencing cranial ossification[59]. In aggregate, both SHH and IHH are found to be crucial regulators of osteogenesis and, therefore, of importance in early craniofacial development.

Clinical Implications

Disruption of SHH signaling in humans is associated with a number of craniofacial defects, such as holoprosencephaly (loss of function) and nevoid basal cell carcinoma syndrome (gain of function)[60,61]. In clinical studies involving familial forms of holopresencephaly, SHH gene mutations are found in as much as 23% of affected families, significantly more than the 1% of non-syndromic mutations[61,62]. Results from a recent study by Kurosaka et al strongly suggest proper SHH signaling is essential for neural crest cell patterning during normal nasal process growth and fusion, especially via Tfap2a, a transcription factor well known for its critical roles during craniofacial development[63-65]. It is worth noting that disruption of TFAP2A can result in branchio-oculo-facial syndrome in humans, a congenital disease seen with cleft lip/palate[66]. Aberrations at any stage in SHH signaling can result in cleft lip/palate, thus underscoring the signaling complexity necessary for normal nasal process growth and fusion.

Clinical studies have also shown that mutations in the IHH gene are associated with malformations resulting in syndactyly and craniosynostosis[67]. Additional mutations in IHH can also lead to acrocapitofermoral dysplasia, an autosomal recessive skeletal dysplasia that results in shortened or absent middle phalanges[43,68,69]. Interestingly, Wei et al demonstrated that increased signaling of IHH correlated with the severity of osteoarthritis and expression of markers of chondrocyte hypertrophy[70]. Thus, for the clinician, IHH may be a potential therapeutic target of interest to prevent osteoarthritis progression. Deletion of the IHH gene is not currently a therapeutic option in humans, as it has proven lethal in animals[71,72]; however, RNA interference serves as a more suitable method, while also avoiding the severe side effects caused by chemical inhibitors[72-78].

Conclusion

While highly conserved across the different homologues, the HH family of proteins have distinct domains of expression and function, although not without overlap, in the context of palatal and facial development. In the context of skeletogenesis, both SHH and IHH have specific roles in endochondral ossification, and new studies even suggest a role for both in intramembranous ossification as well[46]. Thus, both are required for the process of ossification, although they differ in terms of location and how they elicit their effects. SHH expression is lacking in the facial mesenchyme, and instead is localized to the frontonasal and maxillary cranial suture mesenchyme. By contrast, IHH expression occurs primarily on developing palatine bone, and in most studies is placed in the context of endochondral ossification, playing a key role in inducing cell proliferation and differentiation. Finally, aberrations in the HH signaling pathway results in malformations in craniofacial development, studies of which provide further insight into the patterning and expression profile of the HH pathway.

Acknowledgements

This work was supported by the UCLA Department of Pathology and Laboratory Medicine, the UCLA Daljit S. and Elaine Sarkaria Fellowship award, and the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation.

CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest with regard to the present study.

REFERENCES

1 Fietz MJ, Concordet JP, Barbosa R, et al. The hedgehog gene family in Drosophila and vertebrate development. Dev Suppl. 1994:43-51.

2 Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature. Oct 3 1996;383(6599):407-413.

3 Hayhurst M, McConnell SK. Mouse models of holoprosencephaly. Current opinion in neurology. Apr 2003;16(2):135-141.

4 St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes & development. Aug 15 1999;13(16):2072-2086.

5 Dennis JF, Kurosaka H, Iulianella A, et al. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects. PLoS genetics. 2012;8(10):e1002927.

6 Morava E, Bartsch O, Czako M, et al. Small inherited terminal duplication of 7q with hydrocephalus, cleft palate, joint contractures, and severe hypotonia. Clin Dysmorphol. Apr 2003;12(2):123-127.

7 McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 2003;53:1-114.

8 Ehlen HW, Buelens LA, Vortkamp A. Hedgehog signaling in skeletal development. Birth defects research. Part C, Embryo today: reviews. Sep 2006;78(3):267-279.

9 Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Developmental biology. Nov 1995;172(1):126-138.

10 Ruat M, Roudaut H, Ferent J, Traiffort E. Hedgehog trafficking, cilia and brain functions. Differentiation; research in biological diversity. Feb 2012;83(2):S97-104.

11 James AW, Leucht P, Levi B, et al. Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A. Aug 2010;16(8):2605-2616.

12 Rice R, Spencer-Dene B, Connor EC, et al. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. The Journal of clinical investigation. Jun 2004;113(12):1692-1700.

13 Karp SJ, Schipani E, St-Jacques B, Hunzelman J, Kronenberg H, McMahon AP. Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development. Feb 2000;127(3):543-548.

14 Rice R, Connor E, Rice DP. Expression patterns of Hedgehog signalling pathway members during mouse palate development. Gene expression patterns: GEP. Jan 2006;6(2):206-212.

15 Gritli-Linde A. Molecular control of secondary palate development. Developmental biology. Jan 15 2007;301(2):309-326.

16 Pan A, Chang L, Nguyen A, James AW. A review of hedgehog signaling in cranial bone development. Frontiers in physiology. 2013;4:61.

17 Weed M, Mundlos S, Olsen BR. The role of sonic hedgehog in vertebrate development. Matrix Biol. May 1997;16(2):53-58.

18 Echelard Y, Epstein DJ, St-Jacques B, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. Dec 31 1993;75(7):1417-1430.

19 Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. Oct 30 1980;287(5785):795-801.

20 Kawai Y, Noguchi J, Akiyama K, et al. A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development. Reproduction. Feb 2011;141(2):217-225.

21 Yao HH, Whoriskey W, Capel B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes & development. Jun 1 2002;16(11):1433-1440.

22 Lau CI, Outram SV, Saldana JI, Furmanski AL, Dessens JT, Crompton T. Regulation of murine normal and stress-induced erythropoiesis by Desert Hedgehog. Blood. May 17 2012;119(20):4741-4751.

23 Choy SW, Cheng SH. Hedgehog signaling. Vitam Horm. 2012;88:1-23.

24 Cui W, Wang LH, Wen YY, et al. Expression and regulation mechanisms of Sonic Hedgehog in breast cancer. Cancer Sci. Apr 2010;101(4):927-933.

25 Chung UI, Schipani E, McMahon AP, Kronenberg HM. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest. Feb 2001;107(3):295-304.

26 Cohen MM, Jr. The hedgehog signaling network. American journal of medical genetics. Part A. Nov 15 2003;123A(1):5-28.

27 Hojo H, Ohba S, Taniguchi K, et al. Hedgehog-Gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium. The Journal of biological chemistry. Apr 5 2013;288(14):9924-9932.

28 Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science. Oct 11 1996;274(5285):255-259.

29 Pepinsky RB, Zeng C, Wen D, et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem. May 29 1998;273(22):14037-14045.

30 James AW, Pang S, Askarinam A, et al. Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev. Aug 10 2012;21(12):2170-2178.

31 Huangfu D, Anderson KV. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development. Jan 2006;133(1):3-14.

32 Aberger F, Kern D, Greil R, Hartmann TN. Canonical and noncanonical Hedgehog/GLI signaling in hematological malignancies. Vitam Horm. 2012;88:25-54.

33 Cobourne MT, Green JB. Hedgehog signalling in development of the secondary palate. Front Oral Biol. 2012;16:52-59.

34 Lan Y, Jiang R. Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth. Development. Apr 2009;136(8):1387-1396.

35 Levi B, James AW, Nelson ER, et al. Role of Indian hedgehog signaling in palatal osteogenesis. Plast Reconstr Surg. Mar 2011;127(3):1182-1190.

36 Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. Apr 15 2004;18(8):937-951.

37 Ahlgren SC, Thakur V, Bronner-Fraser M. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci U S A. Aug 6 2002;99(16):10476-10481.

38 Sasaki Y, O’Kane S, Dixon J, Dixon MJ, Ferguson MW. Temporal and spatial expression of Pax9 and Sonic hedgehog during development of normal mouse palates and cleft palates in TGF-beta3 null embryos. Archives of oral biology. Mar 2007;52(3):260-267.

39 Proetzel G, Pawlowski SA, Wiles MV, et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nature genetics. Dec 1995;11(4):409-414.

40 Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development. Sep 2002;129(17):4135-4146.

41 Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature genetics. Apr 1994;6(4):348-356.

42 Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nature genetics. Aug 1996;13(4):417-421.

43 Byrnes AM, Racacho L, Grimsey A, et al. Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog. Eur. J. Hum. Genet. Sep 2009;17(9):1112-1120.

44Liem KF, Jr., Jessell TM, Briscoe J. Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. Development. Nov 2000;127(22):4855-4866.

45 Santagati F, Rijli FM. Cranial neural crest and the building of the vertebrate head. Nat. Rev. Neurosci. Oct 2003;4(10):806-818.

46 Kim HJ, Rice DP, Kettunen PJ, Thesleff I. FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development. Apr 1998;125(7):1241-1251.

47 Hodgkinson JE, Davidson CL, Beresford J, Sharpe PT. Expression of a human homeobox-containing gene is regulated by 1,25(OH)2D3 in bone cells. Biochim. Biophys. Acta. Jul 18 1993;1174(1):11-16.

48 Takahashi K, Nuckolls GH, Takahashi I, et al. Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells. Dev. Dyn. Oct 2001;222(2):252-262.

49 Towler DA, Bennett CD, Rodan GA. Activity of the rat osteocalcin basal promoter in osteoblastic cells is dependent upon homeodomain and CP1 binding motifs. Mol. Endocrinol. May 1994;8(5):614-624.

50 Alappat S, Zhang ZY, Chen YP. Msx homeobox gene family and craniofacial development. Cell Res. Dec 2003;13(6):429-442.

51 Chong HJ, Young NM, Hu D, et al. Signaling by SHH rescues facial defects following blockade in the brain. Dev. Dyn. Feb 2012;241(2):247-256.

52 Cobourne MT, Xavier GM, Depew M, et al. Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome. Developmental biology. Jul 1 2009;331(1):38-49.

53 Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatologic clinics. Jan 1995;13(1):113-125.

54 Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. The New England journal of medicine. May 5 1960;262:908-912.

55 Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. Jun 14 1996;85(6):841-851.

56 Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. Jun 14 1996;272(5268):1668-1671.

57 Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A. Medulloblastoma: from molecular pathology to therapy. Clinical cancer research: an official journal of the American Association for Cancer Research. Feb 15 2008;14(4):971-976.

58 Nott RL, Stelnicki EJ, Mack JA, Ben Y, Mitchell R, Mooney MP. Changes in the protein expression of hedgehog and patched-1 in perisutural tissues induced by cranial distraction. Plast. Reconstr. Surg. Aug 2002;110(2):523-532.

59 Lenton K, James AW, Manu A, et al. Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling. Genesis. Oct 2011;49(10):784-796.

60 Odent S, Atti-Bitach T, Blayau M, et al. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum. Mol. Genet. Sep 1999;8(9):1683-1689.

61 Ming JE, Roessler E, Muenke M. Human developmental disorders and the Sonic hedgehog pathway. Mol. Med. Today. Aug 1998;4(8):343-349.

62 Roessler E, Ward DE, Gaudenz K, et al. Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly. Hum. Genet. Aug 1997;100(2):172-181.

63 Kurosaka H, Iulianella A, Williams T, Trainor PA. Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis. J. Clin. Invest. Apr 2014;124(4):1660-1671.

64 Mitchell PJ, Timmons PM, Hebert JM, Rigby PW, Tjian R. Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev. Jan 1991;5(1):105-119.

65Zhang J, Hagopian-Donaldson S, Serbedzija G, et al. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature. May 16 1996;381(6579):238-241.

66 Milunsky JM, Maher TA, Zhao G, et al. TFAP2A mutations result in branchio-oculo-facial syndrome. Am. J. Hum. Genet. May 2008;82(5):1171-1177.

67 Klopocki E, Lohan S, Brancati F, et al. Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. Am. J. Hum. Genet. Jan 7 2011;88(1):70-75.

68 Gao B, Guo J, She C, et al. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat. Genet. Aug 2001;28(4):386-388.

69 Hellemans J, Coucke PJ, Giedion A, et al. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am. J. Hum. Genet. Apr 2003;72(4):1040-1046.

70 Wei F, Zhou J, Wei X, et al. Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthritis Cartilage. Jul 2012;20(7):755-763.

71 Razzaque MS, Soegiarto DW, Chang D, Long F, Lanske B. Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation. J. Pathol. Dec 2005;207(4):453-461.

72 Zhou J, Wei X, Wei L. Indian Hedgehog, a critical modulator in osteoarthritis, could be a potential therapeutic target for attenuating cartilage degeneration disease. Connect. Tissue Res. Aug 2014;55(4):257-261.

73 Zhou J, Chen Q, Lanske B, et al. Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl/fl mice. Arthritis Res. Ther. 2014;16(1):R11.

74 Coventry S, Kapur RP, Siebert JR. Cyclopamine-induced holoprosencephaly and associated craniofacial malformations in the golden hamster: anatomic and molecular events. Pediatr. Dev. Pathol. Jan-Feb 1998;1(1):29-41.

75 Cordero D, Marcucio R, Hu D, Gaffield W, Tapadia M, Helms JA. Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J. Clin. Invest. Aug 2004;114(4):485-494.

76 Lipinski RJ, Dengler E, Kiehn M, Peterson RE, Bushman W. Identification and characterization of several dietary alkaloids as weak inhibitors of hedgehog signaling. Toxicol. Sci. Dec 2007;100(2):456-463.

77 Lipinski RJ, Hutson PR, Hannam PW, et al. Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol. Sci. Jul 2008;104(1):189-197.

78 Lipinski RJ, Song C, Sulik KK, et al. Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications. Birth Defects Res. A Clin. Mol. Teratol. Apr 2010;88(4):232-240.

Peer reviewer: Bruno Ramos Chrcanovic, Malmö University, Faculty of Odontology, Department of Prosthodontics, Carl Gustavs väg 34, SE-205 06, Malmö, Sweden.

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.