A Rabbit Model of Craniosynostosis
Mark P. Mooney, Ph.D.
Associate Professor of Oral Medicine and Pathology,
Anthropology, Plastic Surgery, and Orthodontics
University of Pittsburgh
Pittsburgh, Pennsylvania
 
Although great strides have been made in identifying
the etiology of a number of human craniosynostotic syndromes,
pathogenic mechanisms for these conditions are still
unclear, due in part to the lack of a genetic animal
model with primary craniosynostosis. Recently we have
developed an inbred colony of rabbits with familial
coronal suture synostosis and have begun to systematically
characterize these rabbits. Data will be presented related
to the genetics, craniofacial dysmorphology, coronal
suture pathology, compensatory cranial vault and cranial
base growth patterns, and preliminary molecular data
on sutures and perisutural tissues from affected New
Zealand White rabbits with simple, nonsyndromic, familial
craniosynostosis.
In general, results from these studies revealed that:
1) Conception rate, litter size, gestation length, and
postcranial skeletal morphology were all normal in synostosed
rabbits compared to wild-type controls; 2) No gross
chromosomal abnormalities were noted from karyotype
analysis; 3) The craniosynostosis. seen in this pedigree
is inherited in an autosomal dominant fashion with reduced
penetrance and variable expression as assessed by segregation
rates; 4) Coronal suture fusion begins early during
suture morphogenesis (between 21 and 25 days of gestation),
is preceded by extensive ossification and significant
thickening of the osteogenic fronts of the frontal and
parietal bones, and radiates mediolaterally from a single
focal point on the endocortical side in the middle of
the coronal suture-, 5) Cranial vault, cranial base,
and brain growth abnormalities all developed in the
postsynostotic period, secondary to coronal suture synostosis;
6) The dura mater from synostosed rabbits may be providing
local, abnormal biochemical signals to the calvaria,
resulting in excessive ossification and premature suture
fusion, and these abnormal signals continue to be provided
long after initial synostosis, 7) There were significantly
more osteoblasts and osteocytes along the osteogenic
fronts in synostosed rabbits compared to wild-type controls,
and; 8) There are differential immunoreactivity patterns
of three TGF-B isoforms in the perisutural tissues (dura
mater, sutural ligament, osteogenic fronts, and periosteum)
between wild-type and synostosed coronal sutures.
Results from this series of studies suggest that the
congenital craniosynostosis. in this rabbit model is
familial, localized primarily to the calvaria, and probably
results from enhanced osteoblast mitogenesis and an
excess of bony matrix deposition at the osteogenic fronts.
These findings are consistent with an aberrant TGF-B-expression
model of craniosynostosis. (Opperman et al., 1997; 1998;
Roth et al., 1997; Most et al., 1998). Future research
is in progress to identify the specific genetic mutation,
further characterize the complex biochemical interactions
underlying suture dysmorphogenesis, and develop cytokine
therapy protocols to prevent postoperative resynostosis
in human infants with familial, nonsyndromic craniosynostosis.
Selected Craniosynostotic Rabbit Bibliography
Burrows AM, Mooney MP, Smith TD, Losken HW, Siegel MI.
Growth of the cranial vault in rabbits with congenital
coronal suture synostosis. Cleft Palate - Cramofac J
1995; 32: 235-246.
Burrows AM, Mooney MP, Smith TD, Losken HW, Siegel MI.
Development of plagiocephaly in rabbits with unicoronal
synostosis. J. Neurosurg 1996, 85: 929-936.
Burrows AM, Caruso KA, Mooney MP, Smith TD, Losken HW,
Siegel MI. Sutural bone frequency in synostotic rabbit
crania. Amer J Phys Anthr 1997; 102: 555-563.
Burrows AM, Mooney MP, Smith TD, Losken HW, Siegel MI.
Growth of the cranial vault in rabbits with congenital
coronal suture synostosis. In: Miller S.H., Yearbook
of Plastic, Reconstructive, and Aesthetic Surgery. Mosby-
Yearbook, Inc., Chicago, 1997, 2-4.
Burrows AM, O'Loughlin VD, Smith TD, Mooney MP, Losken
HW, Siegel MI. Comparative dural venous sinus morphology
in coronal synostosis. Amer J Phys Anthrop 1998; Suppl
26; 116.
Burrows, A.M., Richtsmeier, J.T., Mooney, M.P., Smith,
T.D., Losken, H.W., Siegel, M.I. Threedimensional analysis
of cramofacial form in a familial rabbit model of nonsyndromic
coronal suture synostosis using Euclidean distance matrix
analysis. Cleft Palate-Cramofacial J., 1999; 36: 196-206.
Cooper GM, Mooney MP, Burrows AM, Smith TD, Dechant
JJ, Losken HW. Marsh JL, Siegel MI. Brain growth rates
in craniosynostotic rabbits. Cleft Palate-Cranio facial
J 1999-1 36; 314-321.
Dechant JJ, Mooney MP, Cooper GM, Smith TD, Losken HW,
Mathijssen IMJ, Siegel MI. Positional changes in the
frontoparietal ossification centers in perinatal craniosynostotic
rabbits. J Cramofac Gen Devel Biol, 1999-1 19: 64-74.
Etzel K, Owens M, Koepsel R, Losken HW, Siegel MI, Mooney
M.P. Biomechanical strain and collagen I expression
in craniosynostotic rabbits. J Dent Res 1997; 76 (special
issue): 366.
Fellows-Mayle W, Mooney MP, Dechant J, Losken HW, Cooper
GM, Burrows AM, Smith TD, Pollack 1, Siegel MI. Longitudinal
intracranial pressure changes in craniosynostotic rabbits.
Cleft Palate-Cramotac J, 2000, 37: 370-378.
Horutz K, Etzel KR, Owens M, Koepsel R, Smith TD, Burrows
AM, Losken HW, Mooney MP. In situ analysis of Msx2 expression
in craniosynostotic rabbits. J Dent Res 1996-, 7 5 (special
issue); 120.
Kreithen AM, Burrows AM, Mooney MP, Losken HW, Smith
TD, Siegel MI. Influence of congenital cramosynostosis
on coronal suture inderditating length. Amer J Phys
Anthrop 1998; Supplement 26: 144.
Losken HW, Mooney MP, Siegel MI, Lalikos J, Losken A,
Smith T, Burrows A. Breeding and growth studies of a
congenital rabbit model with coronal suture cramosynostosis.
Plast Surg Forum 1993; 16: 200-202.
Losken HW, Fellows-Mayle W, Mooney MP, Dechant J, Burrows
AM, Smith TD, Kreithen AM, Pollack 1. Siegel MI. Intracranial
pressure changes in craniosynostotic rabbits, In: Transactions
of the International Congress on Cleft Palate and Related
Cramofacial Anomalies (Lee, ST ed.), Stamford Press
Pte Ltd, Singapore, 1997, 145-150.
Losken HW, Mooney MP, Opperman LA, Burrows AM, Smith
TD, Dechant J, K-reithen AM, Kapucu R, Ogle RC, Siegel
MI. Coronal suture and dura transplantation in rabbits
with naturally occur-ring cramosynostosis. In: Transactions
of the International Congress on Cleft Palate and Related
Cramofacial Anomalies, (Lee, ST ed.y Stamford Press
Pre Ltd, Singapore, 1997; 117-124.
Losken HW, Mooney MP, Zoldos J, Tschakaloff A, Smith
TD, Burrows AM, Cooper GM, Kapucu MR, Siegel MI. Internal
calvarial bone distraction in rabbits with delayed onset
coronal suture synostosis. Plast Reconstr Surg 1998:
102: 1109-1119.
Losken HW, Mooney MP, Zoldos J, Tschakaloff A, Burrows
AM, Smith TD, Cano G, Arnott R. Sherwood C, Dechant
J, Cooper G, Kapucu R, Siegel MI. Coronal suture response
to distraction osteogenesis in rabbits with delayed
onset coronal suture synostosis. J Cramofacial Surgery,
1999; 10: 29-37.
Mooney MP, Losken HW, Tschakaloff A, Siegel MI, Losken
A, Lalikos JF. Congenital bilateral coronal suture synostosis
in a rabbit and comparisons with experimental models.
Cleft Palate-Cramofac J 1993; 30: 121-128.
Mooney MP, Losken HW, Siegel MI, Lalikos JF, Losken
A, Smith TD, Burrows A. Development of a strain of rabbits
with congenital simple, nonsyndromic coronal suture
synostosis. Part 1. Breeding demographics, inheritance
pattern, and cramofacial anomalies. Cleft Palate-Craniofac
J 1994; 131: 1-7.
Mooney MP, Losken HW, Siegel MI, Lalikos JF, Losken
A, Smith TD, Burrows A. Development of a strain of rabbits
with congenital simple, nonsyndromic coronal suture
synostosis. Part 2. Somatic and cramot-acial growth
patterns. Cleft Palate-Cramofac J 1994; 31: 8-14.
Mooney MP, Aston CE, Siegel MI, Losken HW, Smith TD,
Burrows AM, Wenger SL, Caruso K, Siegel B, Ferrell RE
Cramosynostosis with autosomal dominant transmission
in New Zealand White rabbits. J Cramofac Gen Devel Biol
1996; 16: 52-63.
Mooney MP, Smith TD, Langdon HL, Burrows AM, Stone CE,
Losken 11W, Siegel MI. Coronal suture pathology and
synostotic progression in rabbits with congenital cramostenosis.
Cleft Palate-Craniofac J 1996; 33: 369-378.
Mooney MP, Opperman LA, Losken HW, Burrows AM, Smith
TD, Dechant J, Kreithen AM, Kapucu R, Ogle RC, Siegel
MI. Suture and dura transplantation in rabbits with
cramosynostosis. J Dent Res 1997; 76 (special issue):
256.
Mooney MP, Siegel NIL Burrows AM, Smith TD, Losken HW,
Dechant J, Cooper G, Kapucu MR. A rabbit model of human
familial, nonsyndromic, unicoronal suture synostosis:
Part 1: Synostotic onset, pathology, and sutural growth
patterns. Child's Nervous System 1998; 14: 236-246.
Mooney MP, Siegel MI, Burrows AM, Smith TD, Losken HW,
Dechant J, Cooper G, Fellow-Mayle Kapucu MR, Kapucu
LO. A rabbit model of human familial, nonsyndromic,
unicoronal suture synostosis: Part 2:lntracranial contents,
intracranial volume, and intracranial pressure. Child's
Nervous System 1998; 14: 247-255.
Mooney MP, Burrows AM, Wigginton W, Singhal VK, Losken
HW, Smith TD, Dechant J, Towbin A, Cooper G, Towbin
R, Siegel MI. Intracranial volume in craniosynostotic
rabbits. J Craniofac Surg 1998; 9: 234-239.
Mooney MP, Fellows-Mayle W, Dechant J, Losken HW, Burrows
AM, Smith TD, Cooper GM, Pollack 1, Siegel MI. Increases
in intracranial pressure following coronal suturectomy
in rabbits with cramosynostosis. J Craniofac Surg, 19W
10: 104-111.
Mooney, M.P., Cooper, G.M., Burrows, A.M., Wigginton,
W., Smith, T.D., Dechant, J., R. Mitchell, Losken, H.W.,
Siegel, M.I. Trigonocephaly in rabbits with familial
interfrontal suture synostosis: Multiple effects of
single-suture fusion. Anatomical Record Anatomical Record
2000; 260: 238-251.
Mooney, M.P., Burrows, A.M., Losken, H.W., Opperman,
L.A., Smith, T.D., Dechant, J., Krelthen, A.M., Kapucu,
R., Cooper, G.M., Ogle, R.C., Siegel, M.I. Correction
of coronal suture synostosis using suture and dura mater
allografts in rabbits with familial cramosynostosis.
Cleft Palate Craniofacial J., 2001; in press.
O'Loughlin VD, Burrows AM, Smith TD, Mooney MP, Losken
HW, Siegel MI. Middle meningeal vessel pattern expression
in rabbits with nonsyndromic congenital coronal suture
synostosis. American J. Physical Anthropology 1998;
Supplement 26: 173.
Owens M, Mooney MP, Horutz K, Cillo J, McLean D, Koepsel
R, Smith TD, Burrows AM, Losken HW, Etzel KR. Biornechanical
strain and TGF-P expression in osteoblasts from craniosynostotic
rabbits. J Dent Res 1996; 75 (special issue); 120.
Ozaki, W., Buchman, S.R., Glessner, C.M., Mooney, M.P.,
Losken, H.W. A biornechanical and ultrastructural study
of coronal synostosis. Surgical Forum 1998; 49: 631-633.
Poisson E, Mooney MP, Koepsel R, Cooper GM, Opperman
LA, Sciote JJ. TGF-B isoforrn expression in the perisutural
tissues of craniosynostotic rabbits. J Dent Res, 1999;
78 (special issue): 363.
Putz, D.A., Mooney, M.P., Smith, T.D., Burrows, A.M.,
Cooper, G.M., Dechant, J., Losken, I-I.W., Siegel,
M.I. Growth of the cranial base in craniosynostotic
rabbits following coronal suturectomy. American J. of
Physical Anthropology 2000; Suppl 30: 255-256.
Singhal VK, Mooney MP, Burrows AM, Wigginton W, Losken
HW, Smith TD, Towbin R, Siegel MI. Age related changes
in intracranial volume in craniosynostotic rabbits using
3-D CT scans. Plast Reconstr Surg 1997; 100: 1121- 1128.
Smith TD, Mooney MP, Losken HW, Siegel NIL Burrows A,
Postnatal growth of the cranial base in rabbits with
congenital coronal suture synostosis. J Craniofac Gen
Devel Biol, 1996; 16:107-117,
Stelnicki EJ, Mooney MP, Losken HW, Zoldos J, Burrows
AM, Kapucu R, Siegel MI. Ultrasonic prenatal diagnosis
of coronal suture synostosis. J Craniofac Surg 1997;
8: 252-258.
Yang Z-W, Mooney MP, Ferrell RE. Cloning of the rabbit
FGFR2 gene. Amer. J. Human Genetics, 19W 63 (supplement);
A197.
Yang Z-W, Mooney MP, Ferrell RE. Cloning and sequencing
of the rabbit FGFR2 cDNA. DNA Sequence, 2000; in press.
Zoldos J, Stelnicki E, Losken HW, Mooney MP. Ultrasound
prenatal diagnosis of coronal synostosis. Plas Surg
For, 1996; 19: 115.
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