Concept map from students
The anatomy of palatogenesis
6 wks
12 wks
Cleft lip with or without cleft palate
These patients require multidisciplinary care from birth to adulthood
(21yrs), including nursing, plastic and reconstructive surgery,
Orofacial
clefts
of theotolaryngology,
lip and palate speech
are onetherapy,
of the most
prevalent
maxillofacial
surgery,
audiology,
birth
defects in
the
US, with
about 20,400
childrenpediatric
with oral
clefts
psychological
and
genetic
counseling,
orthodontics,
dentistry
born
between 1999 and 2001 (Centers for Disease Control and Prevention, 2006).
and etc.
Epidemiology: 6,800 per year (19 per day); 1 in 700 live births
Surgery
15
Cleft Palate Anatomy
Z-plasty
Submucosal cleft palate
K14-Cre;Tgfbr2fl/fl
NB
Functional Significance of
Soft Palate Muscles
Functional
separation
of the
digestive
and
respiratory
passages
The Soft
Palate
Newborn
Syndromic Association
• 10-15% with CL/CP
• Up to 50% with CP
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Craniofacial Team
Audiologist
Pediatric Dentist
Pediatric Pulmonologist
Pediatrician
Speech Pathologist
Orthodontist
Social Worker
Pediatric psychologist
Plastic Surgeon
Oral Surgeon
Otolaryngologist
Craniofacial Nurse
Geneticist
Ophthalmologist
Cleft Lip and Palate Patient
Cleft Lip Repair
(3 months old)
Cleft Lip/Nose Revision
Cleft Palate Repair
(1 year old)
Pharyngoplasty (speech dependant)
Alveolar bone graft
(7 or 8 years old)
Jaw Surgery
(15 to 20 years old)
10-15 Team
Visits
Cleft Lip Rhinoplasty
(15 to 20 years old)
Genetic intersections of mouse
and human cleft palate study
Mouse cleft
Human
palate models cleft palate
125
MGI data base
25 82
ALX4
CHD7
COL2A1
DHCR7
EFNB1
EYA1
FGFR2
FLNA
FOXE1
GLI3
IRF6
KCNJ2
MSX1
OFD1
RECQL4
RUNX2
SATB2
SIX3
SOX9
TBX1
TCOF1
TFAP2A
TGFBR2
TWIST1
WHSC1
25
Cleft palate in humans
Animal models
Complete cleft of hard and soft palate
Wnt1-Cre;Tgfbr2fl/fl
Partial cleft of soft palate
K14-Cre;Tgfbr2fl/fl
Palatogenesis in mice
E11
E12
E14
E15
E13
E16
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
E13.0 palate
Palate organ culture
A
B
1. Palatal fusion in
vitro and cell
fate analysis
D
2. It provides an
opportunity for
rescue
experiment
C
TGF-b signaling and palatogenesis
TGF-b mutation and non-syndromic
cleft palate
Lidral et al., 1998 Am J. Hum Genet
TGF-b receptor mutation and cleft palate
Loeys et al., 2005, Nature Genetics 37, 275-281
Cleft palate in humans
Animal models
Complete cleft of hard and soft palate
Wnt1-Cre;Tgfbr2fl/fl
Partial cleft of soft palate
K14-Cre;Tgfbr2fl/fl
Major
categories of
cleft palate
TGF-b signaling in
regulating the fate
of
(1) medial edge
epithelium and
(2) cranial neural
crest-derived
mesenchyme
Chai and Maxson, 2006,
Tgfbr2;Wnt1-Cre
Tgfb3-/-, Tgfbr2;K14-Cre
To investigate the TGF-b signaling mechanism
Facts: (1) All Wnt1-Cre;Tgfbr2 CKO mice develop
complete cleft palate.
(2) TGF-b signaling is crucial for cranial neural crest cell
proliferation and palatal shelf growth.
The identification of TGF-b signaling downstream
target genes is essential for the study of TGF-b
signaling mechanism in regulating palatogenesis.
Identification of up-regulated Tgfb2 and Tgfbr3
in Tgfbr2fl/fl;Wnt1-Cre Palate by microarray analyses
E14.5
Ingenuity Pathway Analysis (IPA) software analysis
Up-regulated: 66 genes
Down-regulated: 75 genes
a
Differential expression of Tgfb and
Tgfbr family members
AFFY_ID
Symbol
FDR
Tgfbr2fl/fl;Wnt1
/ Control
1438303_at
Tgfb2
2.07
0.00052*
1450923_at
Tgfb2
1.95
0.00245*
1450922_a_at
Tgfb2
1.76
0.0004*
1423250_a_at
Tgfb2
1.62
0.00014*
1433795_at
Tgfbr3
1.55
0.02718*
45
Marfan’s syndrome type I
--Mutation in FBN1
Marfan’s syndrome type II
Dr. Junichi Iwata
Loeys-Dietz syndrome
Craniofacial malformations, skeletal defects and vascular problems (aneurysms and dissection)
--Mutation gene: TGFBR1 and/or TGFBR2
Mizuguchi et al., (2004) Nature Genetics 36, 855-860
Loeys BL et al. (2005) Nature Genetics 37:275-281.
Loeys BL et al. (2006) N. Engl. J. Med. 355 (8): 788–98.
LeMaire SA et al. (2007) Nature clinical practice. Cardiovascular medicine 4 (3): 167–71.
--Loeys-Dietz syndrome type I (Elevated TGF-b signaling)
With craniofacial features including craniosynostosis, hypertelorism and
cleft palate and/or bifid uvula
--Loeys-Dietz syndrome type II
Without craniofacial features
46
Modulation of TGF-b signaling rescues cleft palate
Dynamic imaging
analysis of palatogenesis
Micro CT
Micro MRI
Scott Fraser
https://www.facebase.org/
NB
microCT and microMRI (merged)
USC
Caltech
Pedro Sanchez
µMRI based 3D reconstruction of palate and tongue