Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes
Susan M Motch Perrine, Tim Stecko, Thomas Neuberger, Ethylin W Jabs, Timothy M Ryan, Joan T Richtsmeier, Susan M Motch Perrine, Tim Stecko, Thomas Neuberger, Ethylin W Jabs, Timothy M Ryan, Joan T Richtsmeier
Abstract
The brain and skull represent a complex arrangement of integrated anatomical structures composed of various cell and tissue types that maintain structural and functional association throughout development. Morphological integration, a concept developed in vertebrate morphology and evolutionary biology, describes the coordinated variation of functionally and developmentally related traits of organisms. Syndromic craniosynostosis is characterized by distinctive changes in skull morphology and perceptible, though less well studied, changes in brain structure and morphology. Using mouse models for craniosynostosis conditions, our group has precisely defined how unique craniosynostosis causing mutations in fibroblast growth factor receptors affect brain and skull morphology and dysgenesis involving coordinated tissue-specific effects of these mutations. Here we examine integration of brain and skull in two mouse models for craniosynostosis: one carrying the FGFR2c C342Y mutation associated with Pfeiffer and Crouzon syndromes and a mouse model carrying the FGFR2 S252W mutation, one of two mutations responsible for two-thirds of Apert syndrome cases. Using linear distances estimated from three-dimensional coordinates of landmarks acquired from dual modality imaging of skull (high resolution micro-computed tomography and magnetic resonance microscopy) of mice at embryonic day 17.5, we confirm variation in brain and skull morphology in Fgfr2cC342Y/+ mice, Fgfr2+/S252W mice, and their unaffected littermates. Mutation-specific variation in neural and cranial tissue notwithstanding, patterns of integration of brain and skull differed only subtly between mice carrying either the FGFR2c C342Y or the FGFR2 S252W mutation and their unaffected littermates. However, statistically significant and substantial differences in morphological integration of brain and skull were revealed between the two mutant mouse models, each maintained on a different strain. Relative to the effects of disease-associated mutations, our results reveal a stronger influence of the background genome on patterns of brain-skull integration and suggest robust genetic, developmental, and evolutionary relationships between neural and skeletal tissues of the head.
Keywords: Apert syndrome; Crouzon syndrome; brain; craniofacial; craniosynostosis; development; morphological integration; skull.
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References
- Aldridge K., Hill C. A., Austin J. R., Percival C., Martinez-Abadias N., Neuberger T., et al. . (2010). Brain phenotypes in two FGFR2 mouse models for Apert syndrome. Dev. Dyn. 239, 987–997. 10.1002/dvdy.22218
- Anderson P. J., Netherway D. J., Abbott A. H., Cox T., Roscioli T., David D. J. (2004). Analysis of intracranial volume in apert syndrome genotypes. Pediatr. Neurosurg. 40, 161–164. 10.1159/000081933
- Balanoff A. M., Smaers J. B., Turner A. H. (2016). Brain modularity across the theropod-bird transition: testing the influence of flight on neuroanatomical variation. J. Anat. 229, 204–214. 10.1111/joa.12403
- Becker D. B., Petersen J. D., Kane A. A., Cradock M. M., Pilgram T. K., Marsh J. L. (2005). Speech, cognitive, and behavioral outcomes in nonsyndromic craniosynostosis: Plast. Reconstr. Surg. 116, 400–407. 10.1097/01.prs.0000172763.71043.b8
- Blank C. E. (1959). Apert's syndrome (a type of acrocephalosyndactyly)–observations on a British series of thirty-nine cases. Ann. Hum. Genet. 24, 151–164. 10.1111/j.1469-1809.1959.tb01728.x
- Bookstein F. (1991). Morphometric Tools for Landmark data: Geometry and Biology. Cambridge: Cambridge University Press.
- Bristol R. E., Lekovic G. P., Rekate H. L. (2004). The effects of craniosynostosis on the brain with respect to intracranial pressure. Semin. Pediatr. Neurol. 11, 262–267. 10.1016/j.spen.2004.11.001
- Bruner E. (2004). Geometric morphometrics and paleoneurology: brain shape evolution in the genus homo. J. Hum. Evol. 47, 279–303. 10.1016/j.jhevol.2004.03.009
- Bruner E., Amano H., de la Cuétara J. M., Ogihara N. (2015). The brain and the braincase: a spatial analysis on the midsagittal profile in adult humans. J. Anat. 227, 268–276. 10.1111/joa.12355
- Chang K.-P., Lai C.-H., Chang C.-H., Lin C.-L., Lai C.-S., Lin S.-D. (2010). Free flap options for reconstruction of complicated scalp and calvarial defects: report of a series of cases and literature review. Microsurgery 30, 13–18. 10.1002/micr.20698
- Chia R., Achilli F., Festing M. F. W., Fisher E. M. C. (2005). The origins and uses of mouse outbred stocks. Nat. Genet. 37, 1181–1186. 10.1038/ng1665
- Cohen M. M., Kreiborg S. (1990). The central nervous system in the Apert syndrome. Am. J. Med. Genet. 35, 36–45. 10.1002/ajmg.1320350108
- Cohen M. M., Kreiborg S. (1991). Agenesis of the corpus callosum. Its associated anomalies and syndromes with special reference to the Apert syndrome. Neurosurg. Clin. N Am. 2, 565–568.
- Cohen M. M., Kreiborg S. (1994). Cranial size and configuration in apert syndrome. J. Craniofac. Genet. Dev. Biol. 14, 153–162.
- Cohen M. M., MacLean R. (2000). Craniosynostosis: Diagnosis, Evaluation, and Management. New York, NY: Oxford University Press.
- Cole T. M. (2002). Windows-Based Software for Bootstrap-Based Comparison of Morphological Integration Patterns. Kansas City, MO: University of Missouri-Kansas City School of Medicine.
- Cole T. M., Lele S. (2002). Bootstrap-based methods for comparing morphological integration patterns. Am. J. Phys. Anthr. 34:55 10.1002/ajpa.21583
- Da Costa A. C., Walters I., Savarirayan R., Anderson V. A., Wrennall J. A., Meara J. G. (2006). Intellectual outcomes in children and adolescents with syndromic and nonsyndromic craniosynostosis: Plast. Reconstr. Surg. 118, 175–181. 10.1097/01.prs.0000221009.93022.50
- Darroch J., Mosimann J. (1985). Canonical and principal components of shape. Biometrika 72, 241–252. 10.1093/biomet/72.2.241
- de Leon G., de Leon G., Grover W., Aaeri N., Alburger P. (1987). Agenesis of the corpus callosum and limbic malformation in apert syndrome (type I acrocephalosyndactyly). Arch. Neurol. 44, 979–982. 10.1001/archneur.1987.00520210073023
- Dryden I., Mardia K. (1998). Statsistical Shape Analysis. Chichester: John Wiley and Sons.
- Eswarakumar V. P., Horowitz M. C., Locklin R., Morriss-Kay G. M., Lonai P. (2004). A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proc. Natl. Acad. Sci. U.S.A. 101, 12555–12560. 10.1073/pnas.0405031101
- Falsetti A., Jungers W., Cole T. M. (1993). Morphometrics of the callitrichid forelimb: a case study in size and shape. Int. J. Primatol. 14, 551–572. 10.1007/BF02215447
- Fearon J. A., McLaughlin E. B., Kolar J. C. (2006). Sagittal craniosynostosis: surgical outcomes and long-term growth. Plast. Reconstr. Surg. 117, 532–541. 10.1097/01.prs.0000200774.31311.09
- Fernandes M. B. L., Maximino L. P., Perosa G. B., Abramides D. V. M., Passos-Bueno M. R., Yacubian-Fernandes A. (2016). Apert and crouzon syndromes-cognitive development, brain abnormalities, and molecular aspects. Am. J. Med. Genet. A. 170, 1532–1537. 10.1002/ajmg.a.37640
- Flaherty K., Singh N., Richtsmeier J. (2016). Understanding craniosynostosis as a growth disorder. Wiley Interdiscip. Rev. Dev. Biol. 5, 429–459. 10.1002/wdev.227
- Garzón-Alvarado D. A., González A., Gutiérrez M. L. (2013). Growth of the flat bones of the membranous neurocranium: a computational model. Comput. Methods Programs Biomed. 112, 655–664. 10.1016/j.cmpb.2013.07.027
- Gosain A., McCarthy J., Glatt P., Staffenberg D., Hoffman J. (1995). A study of intracranial volume in apert syndrome. Plast. Reconstr. Surg. 95, 284–295. 10.1097/00006534-199502000-00008
- Gower J. (1975). Generalized procrustes analysis. Psychometrika 40:33 10.1007/BF02291478
- Hallgrimsson B., Jamniczky H., Young N. M., Rolian C., Parsons T. E., Boughner J. C., et al. . (2009). Deciphering the palimpsest: studying the relationship between morphological integration and phenotypic covariation. Evol. Biol. 36, 355–376. 10.1007/s11692-009-9076-5
- Hashim P. W., Patel A., Yang J. F., Travieso R., Terner J., Losee J. E., et al. . (2014). The effects of whole-vault cranioplasty versus strip craniectomy on long-term neuropsychological outcomes in sagittal craniosynostosis: Plast. Reconstr. Surg. 134, 491–501. 10.1097/PRS.0000000000000420
- Hébert J. M. (2011). FGFs: neurodevelopment's jack-of-all-trades – how do they do it? Front. Neurosci. 5:133. 10.3389/fnins.2011.00133
- Heuzé Y., Holmes G., Peter I., Richtsmeier J., Jabs E. W. (2014). Closing the gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. Curr. Genet. Med. Rep. 2, 135–145. 10.1007/s40142-014-0042-x
- Honeycutt J. (2014). Endoscopic-assisted craniosynostosis surgery. Semin. Plast. Surg. 28, 144–149. 10.1055/s-0034-1384810
- Ishii M. (2003). Msx2 and Twist cooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault. Development 130, 6131–6142. 10.1242/dev.00793
- Jungers W., Cole T. M., Owsely D. (1988). Multivariate-analysis of relative growth in the limb bones of Arikara Indians. Growth Dev. Aging 52, 241–252.
- Kapp-Simon K. A. (1998). Mental development and learning disorders in children with single suture craniosynostosis. Cleft Palate. Craniofac. J. 35, 197–203. 10.1597/1545-1569(1998)035<0197:MDALDI>;2
- Kapp-Simon K. A., Figueroa A., Jocher C. A., Schafer M. (1993). Longitudinal assessment of mental development in infants with nonsyndromic craniosynostosis with and without cranial release and reconstruction. Plast. Reconstr. Surg. 92, 831–839. 10.1097/00006534-199392050-00008
- Kapp-Simon K. A., Speltz M. L., Cunningham M. L., Patel P. K., Tomita T. (2007). Neurodevelopment of children with single suture craniosynostosis: a review. Childs Nerv. Syst. 23, 269–281. 10.1007/s00381-006-0251-z
- Kawasaki K., Richtsmeier J. (2017a). Association of the chondrocranium and dermatocranium in early skull development, in Building Bones: Early Bone Development Informing Anthropological Inquiry Cambridge Studies in Biological and Evolutionary Anthropology. eds Percival C., Richtsmeier J. (Cambridge, UK: Cambridge University Press; ), 52–78.
- Kawasaki K., Richtsmeier J. (2017b). Appendix to Chapter 3, in Building Bones: Bone Formation and Development in Anthropology Cambridge Studies in Biological and Evolutionary Anthropology, eds Percival C., Richtsmeier J. (Cambridge, UK: Cambridge University Press; ), 303–315.
- Klingenberg C. P. (2008). Morphological integration and developmental modularity. Annu. Rev. Ecol. Evol. Syst. 39, 115–132. 10.1146/annurev.ecolsys.37.091305.110054
- Lauritzen C., Sugawara Y., Kocabalkan O., Olsson R. (1998). Spring mediated dynamic craniofacial reshaping: case report. Scand. J. Plast. Reconstr. Surg. Hand Surg. 32, 331–338. 10.1080/02844319850158697
- Lee C., Richtsmeier J., Kraft R. H. (2015). A computational analysis of bone formation in the cranial vault in the mouse. Front. Bioeng. Biotechnol. 3:24. 10.3389/fbioe.2015.00024
- Lee C., Richtsmeier J., Kraft R. H. (2017). A computational analysis of bone formation in the cranial vault using a coupled reaction-diffusion-strain model. J. Mech. Med. Biol. 17:1750073 10.1142/S0219519417500737
- Lefebvre A., Travis F., Arndt E. M., Munro I. R. (1959). A psychiatric profile before and after reconstructive surgery in children with apert's syndrome. Br. J. Plast. Surg. 24, 151–164.
- Lele S., McCulloch C. E. (2002). Invariance, identifiability, and morphometrics. J. Am. Stat. Assoc. 97, 796–806. 10.1198/016214502388618609
- Lele S., Richtsmeier J. (2001). An Invariant Approach to Statistical Analysis of Shapes. Boca Raton, FL: Chapman and Hall-CRC Press Interdisciplinary studies in statistics.
- Long F. (2011). Building strong bones: molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol. 13, 27–38. 10.1038/nrm3254
- Martínez-Abadías N., Heuzé Y., Wang Y., Jabs E. W., Aldridge K., Richtsmeier J. (2011). FGF/FGFR Signaling coordinates skull development by modulating magnitude of morphological Integration: evidence from apert syndrome mouse models. PLoS ONE 6:e26425. 10.1371/journal.pone.0026425
- Martínez-Abadías N., Holmes G., Pankratz T., Wang Y., Zhou X., Jabs E. W., et al. . (2013b). From shape to cells: mouse models reveal mechanisms altering palate development in apert syndrome. Dis. Model. Mech. 6, 768–779. 10.1242/dmm.010397
- Martínez-Abadías N., Motch S. M., Pankratz T. L., Wang Y., Aldridge K., Jabs E. W., et al. . (2013a). Tissue-specific responses to aberrant FGF signaling in complex head phenotypes. Dev. Dyn. 242, 80–94. 10.1002/dvdy.23903
- Martínez-Abadías N., Percival C., Aldridge K., Hill C. A., Ryan T., Sirivunnabood S., et al. . (2010). Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth. Dev. Dyn. 239, 3058–3071. 10.1002/dvdy.22414
- Mehta V. A., Bettegowda C., Jallo G. I., Ahn E. S. (2010). The evolution of surgical management for craniosynostosis. Neurosurg. Focus 29:E5. 10.3171/2010.9.focus10204
- Mohr G., Hoffman J. H., Munro I., Hendrick B. E., Humphreys R. P. (1978). Surgical Management of Unilateral and Bilateral Coronal Craniosynostosis: 21 Years of Experience. LWW. Available online at: (Accessed April 6, 2017).
- Moosa S., Wollnik B. (2016). Altered FGF signalling in congenital craniofacial and skeletal disorders. Semin. Cell Dev. Biol. 53, 115–125. 10.1016/j.semcdb.2015.12.005
- Moss M. L., Young R. W. (1960). A functional approach to craniology. Am. J. Phys. Anthropol. 18, 281–292. 10.1002/ajpa.1330180406
- Motch Perrine S. M. M., Cole T. M., Martínez-Abadías N., Aldridge K., Jabs E. W., Richtsmeier J. (2014). Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice. BMC Dev. Biol. 14:8. 10.1186/1471-213X-14-8
- Neben C. L., Merrill A. E. (2015). Signaling Pathways in Craniofacial Development: Insights from Rare Skeletal Disorders. Curr. Top. Dev. Biol, 115, 493–542. 10.1016/bs.ctdb.2015.09.005
- Nieman B. J., Blank M. C., Roman B. B., Henkelman R. M., Millen K. J. (2012). If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse. Physiol. Genomics 44, 992–1002. 10.1152/physiolgenomics.00093.2012
- Olson E., Miller R. (1958). Morphological Integration. Chicago, IL: University of Chicago.
- Ornitz D. M. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16, 1446–1465. 10.1101/gad.990702
- Parsons T. E., Schmidt E. J., Boughner J. C., Jamniczky H. A., Marcucio R. S., Hallgrímsson B. (2011). Epigenetic integration of the developing brain and face. Dev. Dyn. 240, 2233–2244. 10.1002/dvdy.22729
- Percival C. J., Liberton D. K., Pardo-Manuel de Villena F., Spritz R., Marcucio R., Hallgrímsson B. (2016). Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the collaborative Cross. J. Anat. 228, 96–112. 10.1111/joa.12382
- Perlyn C., DeLeon V. B., Babbs C., Govier D., Burell L., Darvann T., et al. . (2006). The craniofacial phenotype of the Crouzon mouse: analysis of a model for syndromic craniosynostosis using three-dimensional MicroCT. Cleft Palate Craniofac. J. 43, 740–748. 10.1597/05-212
- Pooh R. K., Nakagawa Y., Pooh K. H., Nagamachi N. (1999). Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome. Ultrasound Obstet. Gynecol. 13, 274–280. 10.1046/j.1469-0705.1999.13040274.x
- Porto A., de Oliveira F. B., Shirai L. T., De Conto V., Marroig G. (2009). The evolution of modularity in the mammalian skull I: morphological integration patterns and magnitudes. Evol. Biol. 36, 118–135. 10.1007/s11692-008-9038-3
- Posnick J., Armstrong D., Bite U. (1995). Crouzon and apert syndromes: intracranial volume measurements before and after cranio-orbital reshaping in childhood. Plast. Reconstr. Surg. 96, 539–548. 10.1097/00006534-199509000-00004
- Pruzansky S. (1982). Craniofacial surgery: the experiment on nature's experiment. Review of three patients operated by Paul Tessier. Eur. J. Orthod. 4, 151–171. 10.1093/ejo/4.3.151
- Quintero-Rivera F., Robson C. D., Reiss R. E., Levine D., Benson C. B., Mulliken J. B., et al. (2006). Intracranial anomalies detected by imaging studies in 30 patients with apert syndrome. Am. J. Med. Genet. A 140A, 1337–1338. 10.1002/ajmg.a.31277
- Renier D., Arnaud E., Cinalli G., Sebag G., Zerah M., Marchac D. (1996). Prognosis for mental function in apert's syndrome. J. Neurosurg. 85, 66–72. 10.3171/jns.1996.85.1.0066
- Renier D., Lajeunie E., Arnaud E., Marchac D. (2000). Management of craniosynostoses. Childs Nerv. Syst. 16, 645–658. 10.1007/s003810000320
- Rice M. C., O'Brien S. J. (1980). Genetic variance of laboratory outbred Swiss mice. Nature 283, 157–161.
- Richtsmeier J., Aldridge K., DeLeon V. B., Panchal J., Kane A. A., Marsh J. L., et al. (2006). Phenotypic integration of neurocranium and brain. J. Exp. Zoolog. B Mol. Dev. Evol. 306B, 360–378. 10.1002/jez.b.21092
- Richtsmeier J., Deleon V. B., Lele S. (2002). The promise of geometric morphometrics. Am. J. Phys. Anthropol. 119, 63–91. 10.1002/ajpa.10174
- Richtsmeier J., Flaherty K. (2013). Hand in glove: brain and skull in development and dysmorphogenesis. Acta Neuropathol. 125, 469–489. 10.1007/s00401-013-1104-y
- Rightmire G. P. (2013). Homo erectus and Middle Pleistocene hominins: brain size, skull form, and species recognition. J. Hum. Evol. 65, 223–252. 10.1016/j.jhevol.2013.04.008
- Rohlf F., Slice D. (1990). Extensions of the procrustes method for the optimal superimposition of landmarks. Syst. Zool. 39, 40–59. 10.2307/2992207
- Roseman C. C., Weaver T. D., Stringer C. B. (2011). Do modern humans and Neandertals have different patterns of cranial integration? J. Hum. Evol. 60, 684–693. 10.1016/j.jhevol.2010.04.010
- Snyder-Warwick A. K., Perlyn C. A., Pan J., Yu K., Zhang L., Ornitz D. M. (2010). Analysis of a gain-of-function FGFR2 crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate. Proc. Natl. Acad. Sci. U.S.A. 107, 2515–2520. 10.1073/pnas.0913985107
- Thisse B., Thisse C. (2005). Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol. 287, 390–402. 10.1016/j.ydbio.2005.09.011
- Tokumaru A., Barkovich J., Ciricillo S. F., Edwards M. (1996). Skull base and calvarial defomities: association with intracranial changes in craniofacial syndromes. Am. J. Neuroradiol. 17, 619–630.
- Twigg S. R. F., Healy C., Babbs C., Sharpe J. A., Wood W. G., Sharpe P. T., et al. (2009). Skeletal analysis of the Fgfr3P244R mouse, a genetic model for the Muenke craniosynostosis syndrome. Dev. Dyn. 238, 331–342. 10.1002/dvdy.21790
- Wallace I. J. (2013). Physical Activity and Genetics as Determinants of Limb Bone Structure. Ph.D. dissertation, Stony Brook University; Available online at:
- Wallace I., Judex S., Demes B. (2015). Effects of load-bearing exercise on skeletal structure and mechanics differ between outbred populations of mice. Bone 72, 1–8. 10.1016/j.bone.2014.11.013
- Wang Y. (2005). Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse. Development 132, 3537–3548. 10.1242/dev.01914
- Xavier G. M., Seppala M., Barrell W., Birjandi A. A., Geoghegan F., Cobourne M. T. (2016). Hedgehog receptor function during craniofacial development. Dev. Biol. 415, 198–215. 10.1016/j.ydbio.2016.02.009
- Yacubian-Fernandes A., Palhares A., Giglio A., Gabarra R. C., Zanini S., Portela L., et al. . (2004). Apert syndrome: analysis of associated brain malformations and conformational changes determined by surgical treatment. Int. J. Pediatr. Otorhinolaryngol. 31, 116–122. 10.1016/s0150-9861(04)96978-7
- Yacubian-Fernandes A., Palhares A., Giglio A., Gabarra R. C., Zanini S., Portela L., et al. . (2005). Factors involved in the cognitive devleopment. Arq. Neuropsiquiatr. 63, 963–968. 10.1590/S0004-282X2005000600011
- Yaguchi Y., Yu T., Ahmed M. U., Berry M., Mason I., Basson M. A. (2009). Fibroblast growth factor (FGF) gene expression in the developing cerebellum suggests multiple roles for FGF signaling during cerebellar morphogenesis and development. Dev. Dyn. 238, 2058–2072. 10.1002/dvdy.22013
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