CTB Theme 3 Flashcards
what is involved in the establishment of the ‘body plan’
- Fertilisation
- Initially the cells proliferate
- Organisation into a body- gastrulation
- 3 sheets of cells develop- ecoderm, mesorderm and endoderm
- Forms a primitive embryo where a head develops at one end and a tail at the other.
- Correct folding is governed my mesenchymal- epithelial interaction
- Organogenesis- organs form
what are the derivatives of the ectoderm (outer layer)
epidermal cells of skin and oral/dental epithelium
cns- neurone of brain
neural crest- pigment cell and CRANIOFACIAL TISSUES (cartilages, bone, teeth)
what are the derivatives of the mesoderm (middle layer)
notochord bone tissue tubule cell of the kidney red blood cells facial muscle
what are the derivatives of the endoderm (internal layer)
digestive tube
pharynx
respiratory tube
what are the derivatives of germ cells
sperm
egg
what is the period where the embryo is subjected to teratogens which can causes malformations in organ systems
4-12 weeks
what are examples of early head formation defects
Holoprosencephaly
•Facial midline defect due to deficiency in forebrain tissue.
•Caused by mutations in Shh pathway genes.
Anencephaly
•Abnormal brain development due to failure of neural tube closure- c
•Caused by teratogens or malnutrition, e.g.:
-High retinoic acid (Vitamin A) levels can interfere with Hox gene expression
-Folic acid (Vitamin B9) deficiency- can prevent craniofacial diseases
why is folic acid advised for pregnant women
(Vitamin B9)
can prevent craniofacial diseases
outline the development of the head fold
21 day human embryo
The folding of the early embryo is a crucial developmental event. (e.g. head formation).
The plate of the 3 germ layers can be seen, structures start to form.
outline the development of the head and mouth for a 16 day old embryo (1/4)
Three germ layers: Ectoderm, Mesoderm, Endoderm
Expansion of the neural plate- formation of head fold
Cells proliferate
outline the development of the head and mouth for a 18 day old embryo (2/4)
Oropharyngeal membrane develops.
It separates the future mouth (stomodeum) from the pharynx and acts as a transient cell signalling centre to “pattern” the oral cavity- It breaks down eventually so it doesn’t interfere with other development
outline the development of the head and mouth for a 22 day old embryo (3/4)
Formation of the future mouth (stomodeum).
Note the rotation of the heart- more inwards
outline the development of the head and mouth for a 30 day old embryo (4mm) (4/4)
Rudiments (anlagen) of most organs are established!
Oropharyngeal membrane starts to break down.
Yellow tube forms the oesophagus
Pharyngeal arches 1,2,3 become prominent
outline the basic structure of the pharyngeal arches
Each arch is covered externally by ectoderm and internally by endoderm.
The internal mesodermal core becomes infiltrated by migrating cranial neural crest cells that migrate into the pharyngeal arches .
=> 1 nerve, 1 cartilage, 1 artery per arch
outline the formation of neural crest cells
- Neural crest cells are induced molecularly at the border between neuroectoderm (forms brain and spinal cord) and epidermis (forms skin)
- Neural plate invagination and formation of neural folds (spinal column) generates an “open tube”.
- Neural folds fuse to form the neural tube. Neural crest cells begin to migrate along pre-determined pathways.
- Neural crest cells continue migration to their pre- determined destinations and become specialised cell types.
outline how NCCs are specified by opposing gradients of signalling molecules
Neural crest cells are specified at the border between neuroectoderm and epidermis.
Overlapping gradients of BMP4 and WNT6 signalling proteins (“morphogens”) induce the expression of FoxD3 and Slug, two transcription factors necessary for neural crest cell specification and migration.
2 opposing gradients- each cells get different gradients. The cells that get intermediate signals are the neural crest cells
outline how Cranial neural crest cells (CNCs) migrate into pharyngeal arches
The cells at each level of the neural tube know where to migrate
Molecular subdivision- cells express different genes that instruct them to migrate to target region
CNCs migrate along specific pathways from the early brain into the pharyngeal
arches.
Genetic codes (overlapping expression of homeobox transcription factors) determine the identity of CNCs. (pre-patterning vs. local specification of cell fates)
In the head region there are other Homeobox genes
what are the embryonic features involved in facial development
lateral nasal process
medial nasal processes
maxillary process
mandibular process
what is the difference between merger and fusion
Merger: Elimination of a furrow between two processes (by mesenchymal cell proliferation). The cells appear as one continuous structure as it expands, its not 2 things coming together. (e.g. mandibular process)
Fusion: Contact between epithelial cells of two processes triggers fusion of epithelial cell sheets and subsequent elimination of epithelial cells. These are 2 different things
what are the key events in the development of the face (4-5 weeks) (1/3)
Formation and growth of an unpaired frontonasal prominence -
Formation of 2 nasal placodes (epithelial thickenings)
Nasal pit:
Formation of paired nasomedial (medionasal) processes
Formation of paired nasolateral (lateronasal) processes
Formation, growth and merger of the paired mandibular processes- this has already merged in the middle so its one continuous process
Formation and growth of paired maxillary processes (small!)- only grow to the inside
what are the key event in the development of the face (5.5-6 weeks) (2/3)
Recession of frontonasal prominence
Due to strong forward growth of nasomedial (medionasal) processes- causes a relocation back wards of the frontonasal prominence
Growth of nasolateral (lateronasal) processes
Strong growth of maxillary processes
-Formation of nasolacrimal duct, cheek and alar base of nose
what are the key event in the development of the face (7-8 weeks) (3/3)
Merger of nasomedial (medionasal) processes- still like two separate processes.
Further growth of maxillary processes and fusion with nasomedial processes
- Formation of central part of nose, upper lip and primary palate
- Upper lip is formed from maxillary processes laterally and in the midline from the nasomedial processes (philtrum).
Outline a summary of the Contributions to face from facial processes summary
A: Maxillary processes
- Maxilla
- Lateral part of upper lip
B: Mandibular processes
- Mandible
- Lower lip
C: Medial nasal processes
- Medial part of nose
- Medial part of upper lip
- Primary palate
D: Lateral nasal processes
- Lateral part of nose
what causes a median cleft lip (rare)
Failure of merger of medial nasal processes.
what causes a (Bi)lateral cleft lip (rare)
Failure of fusion between maxillary processes and medial nasal processes. (Persistence of bucconasal grooves.)
what causes an Oblique facial cleft (rare)
Failure of fusion between maxillary process and lateral nasal process. (Persistence of nasolacrimal groove).
what causes a Lateral facial cleft (macrostomia)
Failure of merger between mandibular and maxillary process.
Mouth is too big (it is underdevelopled)
what causes a Median mandibular cleft
Failure of merger of mandibular processes
Mild form: Chin dimple!
what is a cleft lip and how can it be managed by Multidisciplinary team approach
associated with cleft palate (because the medionasal process also contributes to the primary palate;
Note protrusion of premaxilla in bilateral cleft lip patient.
Clinical management: Multidisciplinary team approach (Oral surgeon, Orthodontist, Speech therapist, Specialist nurse, Psychologist)
what are the clinical features of Frontonasal dysplasia:
Too much tissue in the frontnasal process
Frontonasal separation
various degrees of excessive tissue in the frontonasal process
what are the clinical features of Treacher Collins syndrome (Mandibulofacial dysostosis)
Hypoplasia of mandible and facial bones (e.g. cheek bones), macrostomia (big mouth), ear malformations, cleft palate, abnormal dentition, slanting of palpebral fissures, eyelid coloboma.
how is Treacher Collins syndrome caused
Failure of neural crest cells to migrate into the craniofacial region. Cells die by apoptosis.
-Heterozygous mutations in Tcof1 geneinvolved in ribosome biogenesis – making of ribsomones that produce proteins.
outline the development of the primary palate from
5-6 weeks
6.5 weeks
7 weeks
5-6 weeks: Nasal pits are relocated inwards towards the oral cavity. (Primary palate forms indirectly by relocation of the nasal pits)
6.5 weeks: A thin oronasal membrane separates the nasal and oral cavities. Brings the 2 epithelia together. Molecular signal centre that needs to be removed once development to be complete.
7 weeks: The oronasal membrane disintegrates and nasal choanae (space that forms the nasal and oral cavities) form.
- Continuous nasal and oral cavities
- The primary palate is formed by the merged medial nasal processes (“intermaxillary process”) that continue to grow inwards into the oral cavity.
what is choanal atresia
Persistence of oronasal membrane
Narrowing or blockage of the nasal airway by tissue-
•Incidence: 1:7,000
-Most common nasal abnormality
- Unknown cause
- Part of syndromes, e.g. CHARGE syndrome
- Variability:
- Unilateral (more common) or bilateral
- Blockage by soft tissue or bone
- Partial (stenosis) or complete
•Treatment:
- At birth: Babies Resuscitation, Intubation, Tracheostomy
- Later: Surgical correction
outline the overview of the development of the secondary palate
•The secondary palate is formed by lateral outgrowths of the maxillary processes
(6-10 weeks) and closes the space between nasal and oral cavities.
•12 weeks: Secondary palate has formed completely and is fused to primary palate.
- Nasal and oral cavities are completely separated allowing breathing and eating.
- Babies with cleft palate can’t breathe while feeding! -cant breathe through their nose
outline the development of the secondary palate at 6 weeks and 7-8 weeks (1/2)
- 6 weeks: The median palatal process (primary palate) has formed as an ingrowth of the merged medionasal processes.
- The lateral palatine processes (palatal shelves) appear as outgrowths from the maxillary processes. They grow downwards on either side of the tongue.
- 7-8 weeks: The palatal shelves elevate above the tongue, but are not fused.
- Downgrowth of the nasal septum (formed from frontonasal prominence and tectoseptal process; primary & secondary nasal septum).
outline the development of the secondary palate at 9 weeks and 12 weeks (2/2)
- 9 weeks: Fusion of palatal shelves in anterior part and fusion with primary palate. Fusion of nasal septum with palatal shelves.
- 12 weeks: Fusion of palatal shelves in posterior part and formation of palatine raphe. Incisive foramen remains for blood vessels and nerves. Uvula forms as posterior projection from the medial soft palate (swallowing; speech; gag reflex; breathing).
outline the Development of the secondary palate – Frontal view
- A: 7 weeks: shelf down-growth on both sides of the tongue.
- B: 8 weeks: shelf elevation (but not fusion) & nasal septum down-growth Hypothesised mechanism: Tongue movement, selective tissue hydration- structure can flip up (GAGs)
- C: 9 weeks: shelf fusion (anterior region) & fusion with nasal septum.
- 10 weeks: Developing palatine processes of maxilla and palatine bone rudiments start to ossify and grow towards the midline (arrows).
- 12 weeks: Palatal bone rudiments meet in midline and fuse. - continuous hard palate
outline the Fusion of palatal shelves
Palatal shelves meet through growth of palatal mesenchymal cells.
- Fusion of the two epithelia to form MES (medial epithelial seam)
- Need to happen only between the 2 palatal shelves
- Palatal shelve epithelia fuse randomly with other palates in the mouth cleft lip
Removal of MES by apoptosis of epithelial cells.
All epithelial cell remnants are re-moved resulting in a continuous secondary palate.
what does Incomplete removal of epithelial remnants result in
palatal cysts- Filled with keratin/soft mucous
Could interfere with denture
outline Developmental causes for cleft secondary palate
Early growth or morphogenetic defect :
- Reduced cell proliferation of mesenchymal cells
- If they elevate they can’t fuse
Premature epithelial fusion:
-Epithelium of palatal shelves fuses with other oral epithelia
Failure of palatal shelf elevation:
-Mechanical obstruction or abnormal cell differentiation in ‘hinge’ region of palatal shelves
Late growth defect:
-Reduced cell proliferation of mesenchymal cells
Secondary effects:
-e.g. abnormally wide head (in craniosynostosis)
Epithelial fusion defects:
-Failure of the epithelium to break down during fusion
what are Common varieties of cleft palate
Most common birth defect:
- Cleft lip (CL/P): 1:1000
- Cleft palate only (CP): 1:2500
Unilateral cleft passing through lip and primary palate.
Bilateral cleft lip and cleft primary palate
Cleft secondary palate only (CP)
- C1: Unilateral (cleft on one side of NS)
- C2: Bilateral (cleft on both sides of NS)
- They relate to the fusion with nasal septum
Bilateral cleft lip and cleft primary& secondary palate
- C1: Unilateral: One shelf fused to nasal septum
- C2: Bilateral: Both palatal shelves not fused with nasal septum (NS)
what are the bones of the hard palate
3 bones that form hard palate: premaxilla palatine process of maxilla and horizontal late of palatine bone
- The primary palate bears the incisor teeth and forms the premaxilla bone.
- The premaxilla fuses with the palatine processes of the maxilla bone (arrows).
- The incisive foramen allows for passage of blood vessels and nerves.
- The palatine processes of the maxilla fuse with the horizontal plates of the palatine bone (arrowheads).
Which teeth are most likely to be missing in the cleft lip area
- Upper lateral incisors- they are closely located to the cleft -no space
- Canines??? – its rarely affected by developmental conditions
- The second premolars are next likely to be missing
what is Torus palatinus
- Benign bone overgrowth; usually in the midline of the hard palate
- No treatment required although ulcers are possible; impact on dentures!
what is the Aetiology of syndromic and isolated CL/P and CP
- 30% of cleft cases are associated with another disease (syndromic)- due to single gene mutation in coding regions
- 70% isolated- genetic predisposition, SNP in gene regulatory region
what are Isolated cases of CLP are usually explained by:
Multifactorial complex aetiology
•Interaction between multiple genes (polygenic)
•Interactions between genetic and environmental factors
-High variability of clinical manifestations (mild to severe)
what are Environmental risk factors for cleft lip/palate
- Deficiencies in maternal diet
- Excessive or insufficient vitamin intake e.g. folic acid
- Alcohol abuse
- Tobacco smoking
- Hypoxia (e.g. living at high altitude) – not enough oxygen increased incidence of clefting disorder- the embryo doesn’t get enough oxygen = underdevelopment .
- Anticonvulsant drugs (epilepsy, neuropathic pain)
- Retinoids (medication, e.g. acne cream)
Teratogens • Nitrate compounds • Organic solvents • Exposure to pesticides • Exposure to lead • Recreational drug use (cocaine, heroin)
what is the pathogenic mechanism associated with syndromic forms
• Mutations in coding sequences usually affect gene function more strongly (including pleiotropic effects in other organs) than mutations in gene-regualtory DNA regions that affect tissue-specific gene expression
what is the signifcance of mutations in the coding sequence
• Genetic modules regulating facial development are re-used during tooth development
outline the Development of the Tongue (1/2)
- Appearance of three PA1-derived swellings in floor of the mouth (4-5th week): The medial tuberculum impar (TI) and two lateral lingual swellings (LLS).
- The LLS quickly enlarge and merge with each other and the TI to form the anterior tongue (66% of tongue mass).
•Posterior tongue (34% of tongue mass) forms from hypobranchial eminence (PA3, PA4) that rapidly overgrows the copula ( a transient swelling of PA2; not visible on this image).
-Terminal sulcus: border between oral (anterior) and pharyngeal (posterior) tongue.
where are the anterior and posterior epitehliums of the tongue derived from
Anterior part- ectoderm
Posterior part-endoderm
outline the Development of the Tongue (2/2)
• The foramen caecum marks the original location of the thyroid primordium at the border between TI and copula.
• 7th week: The thyroid primordium migrates downwards towards the 3rd tracheal cartilage (and stays connected by the thyroglossal duct - during migration. ).
• Epiglottis is formed from posterior part of PA4.
• Tongue muscles are derived from occipital somites which have migrated forward into the tongue. Innervation is in accordance with the origin of pharyngeal arches.
- Tongue muscles formed from the mesoderm
what are the Developmental defects of the tongue
Ankyloglossia (‘Tongue tie’)- Failure of lingual frenulum to regress
Macroglossia
what is Ankyloglossia
(‘Tongue tie’)- Failure of lingual frenulum to regress • Connects tongue to floor of mouth • Impaired tongue movement • Impaired speech and feeding • Surgical correction • Van der Woude Syndrome • Tbx22 gene mutations
what is Macroglossia
- Tongue hyperplasia (too large tongue): Down-Syndrome
- Beckwith-Wiedemann Syndrome
- Acromegaly
- Hypothyroidisms (often associated with)
- Microglossia: Tongue hypoplasia (too small): Less common
what are some Developmental defects of thyroid migration
lingual thyroid-the cells need to migrate downwatds into the neck however some of the cells become stuck-
thyroid tissue
thyroglossal duct sinus
ectopic thyroid tissue - check slides for Common points where the thyroid can get stuck in it’s migration pathway
outline the development of the mandible (1/3)
1: Meckels cartilage has formed ~6 weeks i.u.: two hyaline cartilage rods on either side of the jaw surrounded by fibrous tissue extending from the otic capsule (arrow) to the midline of the merged mandibular arches (arrowhead).
- Provides a framework around which the mandible can form but Meckels cartilage actually contributes little to the mature mandible!
2: Ossification starts at 7 weeks i.u. in a lateral mesenchymal cell condensation near the future mental foramen. Ossification rapidly spreads forwards, upwards and backwards.
outline the development of the mandible (2/3)
3: Ossification of mandible body proceeds. Note the tooth germ
4: Mandible takes the shape of a trough underneath the incisive nerve. Meckel’s cartilage is smaller and alveolar process grows to surround the tooth germ.
5: Meckel’s cartilage is resorbed. Incisive nerve now enclosed in bony canal .
Alveolar process almost surrounds incisor tooth germ
Mandibular bones are not fused in the midline (→ symphysis develops ~10 weeks i.u.).
outline the development of the mandible (3/3)
- Ossification proceeds backwards (“posterior”) to form the ramus (R) of the mandible.- In utero not fused
- Mandible direction diverts from Meckel’s cartilage at the level of the lingula.
(Lingula: Mandibular spine attaching to the sphenomandibular ligament. Located near the entry of inferior alveolar nerve into the body (B) of the mandible (mandibular foramen)).
what is the Fate of Meckel’s cartilage
Most of Meckel’s cartilage eventually degrades and the space is filled with bone, BUT… …it is not endochondral ossification!
What structures are formed from Meckel’s cartilage remnants?
Dorsal remnants ossify to form:
- Incus
- Malleus
- Spine of sphenoid bone – remanants of meckels cartilage (→S-man lig)
Ventral remnants ossify to form:
- Lingula (→S-man lig)
- Mental ossicles (→ Mental protuberance)
what are the Sphenomandibular ligament (S-man lig)
and Sphenomalleolar ligament (S-mall lig) ligaments formed from
perichondrium
what are Secondary cartilages (how do they appear histologically)
Secondary cartilages form later in development (always associated with a membranous bone such as the mandible) and appear histologically different from primary cartilages
-More ecm – specialised function of condoyle
how does meckels cartilage appear histologically
larger cells and less extracellular matrix
what Three secondary cartilages develop (10-14 weeks in utero):
Condylar: ( endo- chondral growth plate)
oGrowth potential until 16-20 years of age
oRole in mandibular growth
Coronoid
(transient: ossified before birth)
Symphyseal
o(“mental ossicle”)
o(ossified within 1-2 years of birth)
outline the Postnatal development of the mandible at birth (1/3)
- Ramus comparatively underdeveloped, mandible not fused, no distinct chin
- mandibular “symphysis” – where 2 mandibular bones meet(not a true symphyseal joint! More like a suture!!)
- no distinct chin
outline the Postnatal development of the mandible at 6 years old (2/3)
- Symphysis completely ossified (closed) (by ~1-2 years); mandible fused (single bone)
- Ramus has grown
outline the Postnatal development of the mandible in an adult (3/3)
- Mental protuberance forms prominent chin after puberty (especially in males)
- Growth by bone remodelling
- Prominent chin
what are the types of joints
Fibrous joint
Cartilaginous joint
Synovial joint
what is a fibrous joint and examples
- Two bones connected by fibres e.g sutures
- Sutures: little or no movement (stability & growth)
- Tooth attachment to alveolar bone by periodontal ligament (=> intrusion and recovery in response to biting forces; “shock absorber”)
what is a Cartilaginous joint and examples
2 types
•Primary: Costochondral junction
-Ribs connected to sternum
-bone and cartilage directly apposed
•Secondary: Pubic symphysis
-Piece of fibre inserted - bone-cartilage-fibres-cartilage-bone
what is a synovial joint and examples
Two bones (each with an articular surface covered by hyaline cartilage) are surrounded by a fibrous capsule that creates a joint cavity filled with synovial fluid.
•TMJ: articular surface covered by fibrous tissue joint cavity is divided by articular disk.
-Allows for significant movement in various directions
what can be seen on the External view of temporomandibular joint (TMJ)
- Condyle- secondary cartilage ossified
- Articular disk- not labelled, divides into compartments
- Disk connected to the lateral ptyergoid which enable translation movements of the TMJ
what are the TMJ motions
Rotation (horizontal) and Translation (forwards-backwards)
outline the movements of the TMJ during
- closed mouth
- opening of mouth
- fully open mouth
Closed mouth: Posterior band of disk is situated above the condyle
Opening of mouth: Condyle translates forward and the intermediate zone becomes the articulating surface.
Fully open mouth: Anterior band of disk may be situated above the condyle-
where does the TMJ develop from
from mesenchymal cells located between mandibular condyle
and mandibular fossa in the temporal bone
- Condensation of mesenchymal cells (like dental papilla)
outline the development of the TMJ
At 12 weeks, two clefts appear in the mesenchyme and form the upper and lower joint cavities (D).
-The intervening mesenchyme becomes the articular disk (arrow).
The joint capsule develops from a mesenchymal condensation surrounding the developing joint.
Initially, the mandibular fossa (C) is flat. (The articular eminence becomes prominent only after tooth eruption)
Clefting of mesenchyme to form the lower joint cavity
Articular eminence fully formed and the mandibular fossa no longer flat
developmental processes assoociated with function
what do Variations of TMJ anatomy depend on
functional requirements for mastication! (e.g. tiger the TMJ looks like a door hinge- they need a strong bite, badger, humans)
outline the features of the TMJ
- A: articular disk
- B: mandibular (glenoid) fossa
- C: condyle
- D: joint capsule
- E: lateral pterygoid muscle
- F: articular eminence
(see image)
outline the Histology of the growing TMJ
Fibrous layer of the condyle provides progenitor cells that form chondrocytes that undergo endochondral ossification (similar to perichondrium in epiphyseal/growth plate).
Fibrous layer of the mandibular fossa contains outer layer (more fibrous → articulation) and inner layer (more cellular);
Articular disc- fibrocartilage, made of fibres with chondrocytes interspaced in the middle - more mobility and stability than a typical fibrous tissue
outline the Growth of the condyle
The cells of the proliferative layer divide and produce new chondrocytes enabling condylar growth.
-Grow rapidly and differentiate into mature chondrocytes that produce cartilage.
Endochondral ossification is similar to the epiphyseal/growth plate. Condylar cartilage can grow up to the age of 16-20 years, and is then fully calcified.
-Chondrocytes will die and osteoblasts move in and deposit bone matrix on top of the cartilage matrix
outline development of The condyle at the end of the growth period
Growing condyle (13 years): enlarged proliferative cell layer
Adult condyle: reduced proliferative cell layer
- Cells of the proliferative layer persist throughout life and can respond to functional changes (“masticatory stress”) by reactivating condylar growth-
- Basis for remodelling of articular surfaces by orthodontic treatment.- most efficient in teenage period when this cell layer is thick and can grow rapidly, it is still possible.
what layers form in the adult condyle
Fibrocartilage and calcified cartilage
outline the The articular eminence formation in adults
Similar organisation as in the condyle but no endochondrally ossified cartilage
- Proliferative zone can also respond to functional changes and induce remodelling
- Note: Thick layer of fibres covering the articular eminence potentially involved in ensuring articulation.(→ articulation)
what is the Synovial membrane
Lines the capsule
Bilayered with folds/villi that protrude into joint cavity and produce synovial fluid. (more folds with increasing age and in pathological conditions- to compensate for production of more fluid if there is an issue in the joint
what is the function of the Temporomandibular ligament
The temporomandibular ligament prevents posterior, inferior, lateral and medial displacement.
- Dislocation can only occur in a forward direction (by slipping of the condyle head over the articular eminence).
what are the muscles of mastication
infrahyoid lateral pterygoid masseter; medial pterygoid suprahyoid temporalis
