A challenge associated with sharing public spaces with animals is the transmission of infection, which requires owners to be vaccinated to ensure protection. Pet owners are encouraged to ensure that they themselves are vaccinated, however, its efficiency is mitigated due to polarising views on the ostensible inoculation that it imposes. Historically speaking, vaccinations are undoubtedly acclaimed to propagate a safer, healthier community, and is marked as the most effective method in combatting infection (Zinsstag 2007, n.p., para. 3). To heighten this notion, The World Health Organizatio (WHO) indicates that in communities where there is a higher proportion of vaccinated individuals, the rate of zoonotic diseases decreases by 43% (Zinsstag 2007, n.p., para. 7). However, the benefits of immunizations are most evidently seen (and is essentially limited to) when herd immunity is achieved. Herd immunity is a form of immunity that occurs when a significant proportion of a population (or herd) is vaccinated, and thus provides a level of protection for unvaccinated individuals or those who have compromised immune systems (Anderson 1990, p. 3, para. 3). As such, this management technique of zoonotic illnesses is heavily reliant on societal willingness towards vaccination, and is thus, fallible. Evidently, efforts need to be shifted towards maximising communal inclination towards vaccination, and resultantly, increasing social security against fatal illnesses. This is especially since social awareness in regards to zoonotic vaccines are fairly minimal (Streefland 2001, p. 9, para. 2). On this note, in regards to immunization coverage in Australia, government-funded vaccinations mean low vaccination rates primarily stem from misconceptions, or rather, a lack of knowledge, of the benefits of vaccinations (Streefland 2001, p. 1, para. 7). Subsequently, ‘societal resistance,’ as aforementioned, has been found to be primarily due to the ‘possession of incorrect knowledge that distorts their perceived risk of vaccination’ (Denovan, 2011). This is especially pertinent because the proportion of unvaccinated individuals is remarkably comprised of adults. As corroboration, in a study conducted by the WHO, ‘of 4.1 million unvaccinated Australians, 92 per cent (3.8 million) are adults, and only a small fraction are children’ (MacIntyre 2017, p. 5, para. 4). As demonstrated, this is especially detrimental to health security because as MacIntyre typifies, ‘adults contribute substantially to ongoing vaccine-preventable diseases’ (MacIntyre, 2017). This is exemplified as ‘48% of all cases of measles that occur in Australia are in those aged 19 years or over’ (Denovan 2011, p. 11, para. 2). Nonetheless, adults’ apprehensive stance towards vaccination may be inherited by their children, and ultimately, transform the healthcare dynamic that is currently relied upon to evade fatal zoonoses. Consequently, shifting sceptical views harboured by society regarding vaccines, specifically by adults, is not only a vital response to zoonoses, but more broadly enhances health security.
An imminent implication of zoonoses is its economic detriment upon society and to the cost of health care. In the case of a zoonotic epidemic, the pet and its owner are not the only victims of this scourge, it has large scale economic repercussions that will be discussed in what follows. For instance, a case study conducted by Food and Agriculture Organization of the United Nations (FAO) indicates that ‘it can affect entire sectors of the livestock industry and reduce human capital’ (Fao.org 2018, p. 5, para. 3). This is depicted in a study conducted by WHO, in which it is estimated that ‘the avian influenza reduced chicken meat production by over one third in China, and that the 2009 swine flu pandemic, which originated in Mexico, infected over 100 million people with a death toll of about 20 000’ (Fao.org 2018, p. 3, para. 6). However, due to limitations in the ‘current zoonotic disease information system,’ the United Nations’ Ministry of Health and Agriculture finds it ‘challenging to generate accurate estimates of the incidence and prevalence of zoonoses, to assess their impact on society, and to measure the benefits of programmes and investments for their prevention, management and control’ (Fao.org 2018, p. 4, para. 1). In other words, there is a lack of structured management and framework in designating public resources to combat zoonoses adequately (Fao.org 2018, p. 3, para. 2). Patently, there is an accelerating call for relevant institutions to curate a defined action plan, within which the economic impact is accurately considered and estimated, and hence, can be appropriately managed. Further, there are costs to the public and private health system, which can overwhelm and eventually exhaust medical resources, inhibiting its ability to manage common health problems that increase susceptibility to emerging epidemics – thus, exacerbating the problem (Bloom 2018, p. 3, para. 6). Ahead of precipitating a volatile health sector, Bloom implies that ‘epidemics force both the ill and their caretakers to miss work or be less effective at their jobs, driving down and disrupting productivity’ (Bloom 2018, p. 8, para. 6). Additionally, erupting apprehensions of infection may result in ‘closed schools, enterprises, commercial establishments, transportation, and public services—all of which disrupt economic and other socially valuable activity’ (Bloom 2018, p. 9, para. 3). Moreover, unease over the extent and/or widespread of even a relatively isolated zoonotic outbreak can result in reduced trade (Bloom 2018, p. 11, para. 2). This is illustrated in ‘a ban imposed by the European Union on exports of British beef lasted 10 years following identification of a mad cow disease outbreak in the United Kingdom, despite relatively low transmission to humans’ (Bloom 2018, p. 3, para.11). Evidently, the economic risks of epidemics are anything but arbitrary, and as such, would hardly differ in the case of a zoonotic outbreak. Even if the health implications of an outbreak are somewhat contained, its economic impact can hastily become amplified. As insinuated by Bloom, ‘Liberia, for example, saw GDP growth decline 8 percentage points from 2013 to 2014 during the recent Ebola outbreak in west Africa, even as the country’s overall death rate fell over the same period’ (Bloom 2018, p. 3, para. 9).’ Moreover, the adverse aftermath of epidemics is not distributed proportionately across the economy (Bloom 2018, p. 3, para. 9). Some sectors may even reap financial benefits, such as ‘pharmaceutical companies that produce vaccines, antibiotics, or other products needed for outbreak’ (Bloom 2018, p. 10, para. 5). On the other hand, ‘Health and life insurance companies are likely to bear heavy costs, at least in the short term, as are livestock producers in the event of an outbreak linked to animals’ (Bloom 2018, p. 3, para. 3). Likewise, Vulnerable populations, particularly those of a lower socioeconomic background, are among those likely to suffer disproportionately, ‘as they may have less access to health care and lower savings to protect against financial catastrophe’ (Bloom 2018, p. 5, para. 8). Therefore, the economic detriment of society amidst outbreaks and epidemics act as an exemplary for zoonoses, and thus alludes to the financial tumult that can ensue as a result. Thus, as explained, the economic penalty of zoonotic infections is as dire, if not more, than the biological ramifications. So, akin to management of other types of risks, the economic risk of ‘health shocks’ can be managed with policies that minimise their detriment, and that equip nations to rapidly respond if they do occur.
As previously mentioned, a conclusive method is essential to counteract the fatality rate of zoonoses; such as a greater collaboration by animal, human and environmental sectors in order to enhance active mechanisms against emerging health threats. One current example of this is being facilitated by Hunter New England Health (HNEH) and a group of GPs in rural NSW who have developed an ‘algorithm tool to assist with diagnosing and treating a range of severe zoonoses, such as; Q fever and brucellosis’ (Gunaratnam 2014, p. 10, para. 4). The urgency of such a tool was discerned when a literature review conducted by the University of Iowa and survey of GPs failed to recount a current management mechanism for zoonoses (Gunaratnam 2014, p. 7, para. 1). Subsequently, ‘all the clinicians involved with the project agreed that such a tool would be helpful, and should be brief and available’ extensively to the public in digital and paper format (Gunaratnam 2014, p. 13, para. 3). Resultantly, ‘the algorithm for the diagnosis and management of common zoonoses has been developed, incorporating the advice and comments of GPs and laboratory and infectious disease specialists’ (Gunaratnam 2014, p. 3, para. 9). While this tool is conducive in curating a clear-cut action plan in the event of a zoonotic outbreak, there are several limitations that should be taken into account and/or considered in the formulation of future algorithms. Firstly, the algorithmic tool is ‘not designed as an exhaustive resource but rather to draw GPs’ attention to the more important elements of diagnosing and managing a patient with brucellosis, leptospirosis or Q fever’ (Gunaratnam 2014, p. 11, para. 3). Moreover, the algorithm was comprised with the presumption that many zoonotic illnesses may present the signs and symptoms that could emulate the three chosen (Gunaratnam 2014, p. 12, para. 2). Another shortcoming is that ‘it was not possible in a single algorithm to capture all zoonotic infections,’ and finally, there is also ‘individual variability in the bodily response to a zoonotic illness’ (Gunaratnam 2014, p. 5, para. 3.) Subsequently, the merit or plausibility of making a substantial investment into a cause that can only be harnessed in a restricted array of cases needs to considered (Gilchrist 2002, p. 1, para. 18). Thus, although HNEH pioneered a sufficient mechanism to combat infections; the factors mentioned above should be encompassed in future tools to maximise the benefits, while maintaining economic sustainability.
Another mechanism to tackle animal-related illnesses is pervasive educational programs at schools that are centralised around pet-related hygiene practises, which are instrumental in minimizing contact with pathogenic agents. There are a multitude of programs targeted at delivering guidance towards safer pet ownership, one of which is The Responsible Pet Ownership Program launched by the Victorian Government. Currently, this is the only government-funded incentive in Australia focalised around pet safety, which speaks volumes about institutional concern in regards to zoonotic infections. As this is a government incentive, there may be a political interest to venerate programs that are essentially necessities. While there is a state government incentive, the RPO Program in place is focalised on pet safety and responsibility (The Victorian Government 2017, p. 1, para. 9), this leaves a substantial gap in education regarding pet hygiene. Resultantly, Animal Health Australia (AHA), a non-for-profit public company, works to provide and training and action plans to students to assist them in the case of a possible zoonotic infection, under the Emergency Animal Disease Response Agreement (EADRA) (Animal Health Australia 2019, p. 1, para. 2). AHA works to ensure that trained personnel are adequately equipped in the event of an emergency animal disease (EAD) response (Animal Health Australia 2019, p. 1, para. 2). Educational programs such as these have been found to reduce morbidity rates by up to 25% in Zimbabwe (McNicholas 2005, p. 1, para. 7). Adversely, as it is not a government-funded organization, their auspicious work is constrained by a lack of funding. Therefore, it would be more propitious for the government to designate pet hygiene educational programs to organizations who specialise in animal welfare, and allocate funding accordingly as opposed to investing money into governmental programs who insufficiently address the core of zoonotic issues – poor hygiene. As a result, a manner in which society can response to emerging zoonoses is educating members of society, particularly vulnerable children, on the prevention of pathogenic transfer and animal safety.
Evidently, there are multitude of management mechanisms to control
zoonotic diseases. While there may be more elaborate, sinuous processes to
inhibit these diseases, ultimately, it is reliant on governmental and/or institutional
initiative. Therefore, the most effective precaution an individual can take is to
simply ensure their pets, their loved ones and they themselves are immunised
against these potentially fatal infections.
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Genetics of Malocclusion
Alhammadi et al performed a review of the literature to determine the distribution of malocclusion across the world, both in permanent and mixed dentitions (Alhammadi et al., 2018). From a pool of 53 studies (they retrieved 2977 from an electronic search), they estimate that the prevalence of Class I type of occlusion is 74.7%, Class II is 19.56% and Class III is 5.93% in permanent dentition. In mixed dentition the prevalence of Class I were 73%, Class II 23% and Class III 4%.
Embryology and postnatal development of the maxilla and mandible
Both the maxilla and the mandible are derived from the first pharyngeal arch (Nanci, 2017) Moreover they develop from paired prominences composed of mesenchyme that can be identified in a 42 days old embryo (Sadler, 2019). The growth of the mandible is assisted by the cartilage of the first pharyngeal arch, the Meckel’s cartilage. This structure has a close positional relationship with the mandible however it does not give rise to bone in the mandible. Instead, the mandible develops from intramembranous ossification and Meckel’s cartilage disintegrate and largely disappear, forming only a portion of the malleus and incus, but not contributing into a significant part of the mandible (Proffit et al., 2018). The process of intramembranous formation of the mandible starts at the sixth week with a condensation of the mesenchyme in the division of the inferior alveolar nerve in the incisor and mental branches (Nanci, 2017). Later, the ossification starts at this condensation, spreading anteriorly towards the midline and posteriorly to the point where the mandibular never divides. The anterior ossification takes place along the lateral aspect of Meckel’s cartilage which leads to the formation of a trough or channel that consist of two plates (one medial and one lateral) that join each other beneath the incisor nerve. This trough of bone extends to the midline where it gets close to the contralateral trough of the contralateral mandibular process. These two ossification centers do not fuse with each other until shortly after birth. Later the through of bone is converted into a canal because of the formation of bone above the nerve. The posterior ossification also takes place along the lateral aspect of Meckel’s cartilage. It extends toward the division of the mandibular nerve into the inferior alveolar and lingual nerve. Moreover, medial and lateral plates of bones develop in relation to teeth germs, starting at the point of division of the mandibular nerve. This phenomenon allows the division of the trough of bone in compartments occupied by teeth germs which are going to be completely surrounded by bone (Nanci, 2017). The ramus of the mandible is also formed by intramembranous ossification of the mesenchyme of the first pharyngeal arch.
In contrast to the embryonic period, postnatally the mandible growths by endochondral activity in the condyle at the temporomandibular joint where hypertrophy, hyperplasia and endochondral replacement occurs in the cartilage that covers the surface of the condyle. The rest of the mandible growth by direct apposition on its surface. Vital staining studies indicate that the principal sites of growth of the postnatal mandible are the posterior surface of the ramus (which allows an increase in the length of the mandible) and the condylar and coronoid process with minimal changes in the body and chin area. When considering this as the frame of references it looks like the mandible is translated downward and forward. However, it grows upward and backward maintaining its contact with the skull.
The maxilla develops entirely intramembranous ossification of the mesenchyme of the maxillary process (Proffit et al., 2018). Its center of ossification appears where the inferior orbital nerve gives the anterosuperior dental nerve. Bone formation spreads from this center posteriorly toward the zygoma, anteriorly toward the incisor region and superiorly to form the frontal process of the maxillary bone. This pattern of bone deposition allows the formation of another trough in relationship with the infraorbital nerve. In addition, bone in relationship with the tooth germs arises from two plates: one medial and one lateral. They are named medial and lateral alveolar plates. The lateral alveolar plate arises from a downward extension of the trough of the infraorbital nerve. The medial alveolar plate forms from the union between the palatal process and the main body of the maxilla. Both, the medial and the lateral alveolar plates will give rise to another trough of bone surrounding tooth germs. Like in the mandible, the tooth germs will be enclosed in bone (Nanci, 2017).
Postnatally the growth of the maxilla is the result of a process of translation of the position of the mandible relative to the cranium and the cranial base and a simultaneous phenomenon of bone surface modelling. The position translation is due to forces arising from the cranial base growth that pushes the maxilla and from bone apposition in the sutures that connect the maxilla to the cranial base and cranium. The modelling process consists of resorption of the anterior surface of the maxilla with apposition of bone in the opposite direction (Proffit et al., 2018).
Syndromes that present malocclusion
A classical syndrome that present malocclusion as a clinical feature is the Crouzon Syndrome (OMIM # 123500) (Glaser et al., 2000). These patients often present hypoplastic maxilla and exophthalmia (Neville et al., 2016). Crouzon syndrome is considered an autosomal dominant disorder that presents craniosynostosis (premature closure of cranial sutures) and it is thought to be caused in part by a mutation in the gene encoding the fibroblast growth factor receptor 2 (FGFR2) on the chromosome 10. The FGFR2 genes encode a tyrosine kinase receptor that has three portions(Johnson and Wilkie, 2011). The first region is an extracellular ligand binding portion composed of three immunoglobulins like domains (IgI, IgII and IgIII). The second region is a transmembrane region and the last one is an intracellular kinase domain (Azoury et al., 2017). It has been suggested that most of the mutation that causes Crouzon syndrome occurs in the third extracellular immunoglobulin-like domain encoded by exons IIIa or IIIc, producing constitutive activation of the receptor (Johnson and Wilkie, 2011). The hypoplastic maxilla phenotype arises from a prenatal fusion of the superior and posterior sutures of the maxilla along the wall of the orbit. This premature fusion of these sutures prevents that the maxilla is translated downward and forward producing severe underdevelopment of the maxilla (Proffit et al., 2018).
Another syndrome that presents a malocclusion as a phenotype is the Apert syndrome (OMIM #101200). Patients affected by the Apert Syndrome also present craniosynostosis, cone-shaped calvarium, Midfacial hypoplasia and several other clinical features (Woods et al., 2015). Studies indicate that 98% Apert syndromes are caused by one of two mutations in the exon IIIa of the FGFR2 gene. This mutation cause an amino acid substitution of a Serine for a Tryptophan in the position 252 or a Proline for an Arginine in the position 253. These two mutations produce an increased affinity and altered specificity of FGFR2 for its ligand the fibroblast growth factor (FGF) (Das and Munshi, 2018).
Treacher Collins syndrome (OMIM #154500) is another case of a syndrome that present malocclusion. This disease follows an autosomal dominant pattern of inheritance and presents a variable phenotype that includes bimaxillary micrognathia and retrognathia in 78% of patients (Kadakia et al., 2014). Most of the mutations occur in the gene TCOF1 in around 78 to 93% of the cases but in around 8% of the patients, the mutations are in the genes POLR1C or POLR1D. Several mutations have been associated with Treacher Collins syndrome and most of them are small frameshift mutations yielding a truncated protein. Studies in animals indicate that the protein produced by the gene TCOF1 attenuate the neural crest cell migration into the craniofacial region. Specifically, it is considered that mutations in TCOF1 affect ribosomal biosynthesis in the neural crest cells that are migrating to the craniofacial regions.
Genes associated with non-syndromic malocclusion
In a study published in 2015, da Fontoura et all evaluate the association of several candidate genes and skeletal malocclusion (da Fontoura et al., 2015). Specifically, they evaluated genes that are known to be expressed in the craniofacial complex, have a genetic linkage to malocclusion or a known role in the etiology of syndromes that present malocclusion. They characterized the phenotypes of 269 patients using cephalometric radiograph. The criteria used are the size of the overjet, the ANB angle, molar/canine angle classification, Witt analysis and the lateral profile of the patient. Considering this high number of dimensions in the phenotypes, the authors performed a principal component analysis. This is a mathematical method that allows transforming this high number of dimensions in just a few. This few dimensions act as a summary of features and are named principal components (PC) (Lever et al., 2017). They identified four principal components that in total explained 69% of the variance among the patients. The PC1 represents vertical discrepancies, from skeletal deep bites to skeletal open bites. The PC2 depicts horizontal discrepancies that vary from convex to concave profiles. The PC3 describes the ramus height, mandibular body size and cranial base orientation. The PC4 explain the variation in the condylar inclination and projection of the chin. Then they search for associations between these PC and the genotypes from the patients. In order to do this, they evaluate the degree of association between single nucleotide polymorphisms (SNP) present in the candidate genes of the patients and each of the four PC. They identified two SNP significantly associated with PC3 and PC4, respectively. The first one is near a gene named TWIST1 and was associated with the PC3. This SNP is associated with a shorter ramus, larger body mandibular body length and a steep anterior cranial base orientation. The second SNP was near a gene called SNAI3 and was associated with PC2. Specifically, it is associated with a severe class II phenotype and a convex profile. The role of TWIST1 in the development of the size of the ramus is also sustained by results obtained in mouse. In order to understand the role of Twist1 in mandibular development, Zhang et al used conditional Knock out of Twist1(Zhang et al., 2012) in a mouse where the expression of Cre recombinase is under the control of an enhancer region of Hand2 (Ruest et al., 2003). This last gene is expressed in post-migratory neural crest cells that populate the mandibular pharyngeal arch. Therefore, when this group of cells express Hand2 the Cre enzyme will be active and it is going to induce the recombination event leading to the knockout of Twist1 in the post-migratory neural crest cells in the mandible. When they analyze the phenotype of pups with this conditional knockout out, the authors identified that the ramal region of the mandible was greatly reduced in size.
Several genes have been associated with mandibular prognathism (MIM #176700) (Chen et al., 2015). For instance, a genome-wide association study identified 6 loci as susceptible regions of mandibular prognathism (Saito et al., 2017) suggesting 6 genes as candidates (Table 1).
Current and future therapy
Malocclusion may be treated with orthognathic surgery. This procedure may be defined as “the surgical repositioning of the maxilla and/or mandible with or without orthodontic repositioning of the teeth, in order to improve dentofacial function and aesthetics (in a stable manner) and health-related quality of life” (Naini et al., 2017). Moreover, patients that present malocclusion may be treated with orthodontic therapy (Abreu, 2018). The utility of knowing which genes may help develop a precision orthodontic treatment in which this genetic information can be used to predict, for instance future growth trajectories (Jheon et al., 2017).
Type of occlusion
Syndromic or non-syndromic
Genetic cause (multi gene, single gene) name of gene
Mutation in FGFR2
(Neville et al., 2016)
Mutation in FGFR2
(Johnson and Wilkie, 2011)
Treacher Collins syndrome
Mutations in TCOF1, POLR1C or POLR1D.
(Kadakia et al., 2014)
(Chen et al., 2015)
(Zebrick et al., 2014)
(da Fontoura et al., 2015)
(da Fontoura et al., 2015)
Loci 1p22.3; gene SSX2IP
(Saito et al., 2017)
Loci 1q32.2; gene PLXNA2
(Saito et al., 2017)
Loci 3q23; gene RASA2
(Saito et al., 2017)
Loci 6q23.2; gene TCF21
(Saito et al., 2017)
Loci 7q11.22; gene CALN1
(Saito et al., 2017)
Loci 15q22.22; gene RORA
(Saito et al., 2017)
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Azoury, S.C., Reddy, S., Shukla, V., Deng, C.X., 2017. Fibroblast Growth Factor Receptor 2 (Int J Biol Sci 13, 1479-1488.
Chen, F., Li, Q., Gu, M., Li, X., Yu, J., Zhang, Y.B., 2015. Identification of a Mutation in FGF23 Involved in Mandibular Prognathism. Sci Rep 5, 11250.
da Fontoura, C.S., Miller, S.F., Wehby, G.L., Amendt, B.A., Holton, N.E., Southard, T.E., Allareddy, V., Moreno Uribe, L.M., 2015. Candidate Gene Analyses of Skeletal Variation in Malocclusion. J Dent Res 94, 913-920.
Das, S., Munshi, A., 2018. Research advances in Apert syndrome. J Oral Biol Craniofac Res 8, 194-199.
Glaser, R.L., Jiang, W., Boyadjiev, S.A., Tran, A.K., Zachary, A.A., Van Maldergem, L., Johnson, D., Walsh, S., Oldridge, M., Wall, S.A., Wilkie, A.O., Jabs, E.W., 2000. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 66, 768-777.
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Johnson, D., Wilkie, A.O., 2011. Craniosynostosis. Eur J Hum Genet 19, 369-376.
Kadakia, S., Helman, S.N., Badhey, A.K., Saman, M., Ducic, Y., 2014. Treacher Collins Syndrome: the genetics of a craniofacial disease. Int J Pediatr Otorhinolaryngol 78, 893-898.
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Ruest, L.B., Dager, M., Yanagisawa, H., Charité, J., Hammer, R.E., Olson, E.N., Yanagisawa, M., Clouthier, D.E., 2003. dHAND-Cre transgenic mice reveal specific potential functions of dHAND during craniofacial development. Dev Biol 257, 263-277.
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Saito, F., Kajii, T.S., Oka, A., Ikuno, K., Iida, J., 2017. Genome-wide association study for mandibular prognathism using microsatellite and pooled DNA method. Am J Orthod Dentofacial Orthop 152, 382-388.
Woods, E., Parekh, S., Evans, R., Moles, D.R., Gill, D., 2015. The dental development in patients with Aperts syndrome. Int J Paediatr Dent 25, 136-143.
Zebrick, B., Teeramongkolgul, T., Nicot, R., Horton, M.J., Raoul, G., Ferri, J., Vieira, A.R., Sciote, J.J., 2014. ACTN3 R577X genotypes associate with Class II and deepbite malocclusions. Am J Orthod Dentofacial Orthop 146, 603-611.
Zhang, Y., Blackwell, E.L., McKnight, M.T., Knutsen, G.R., Vu, W.T., Ruest, L.B., 2012. Specific inactivation of Twist1 in the mandibular arch neural crest cells affects the development of the ramus and reveals interactions with hand2. Dev Dyn 241, 924-940.