Cranio-facial development, instuderingshjälp

## **The human skull**

The cranial skeleton consists of three elements derived from different precursors:

1. The chondrocranium (neurocranium): base of the skull + sensory capsules.
2. The external armor of membrane bones: calvaria or cranial vault.
3. The viscerocranium: support of the jaws.

### The pharyngeal archers (PA)

Five pairs of PA form on either side of the pharyngeal foregut (start E22)

**Each arch has:**

* An outer covering of ectoderm
* An inner covering of endoderm
* A core of mesenchyme derived from the lateral plate mesoderm, the adjacent somitomeres or somites, and from the neural crest.

**Each arch contains:**

* A cartilaginous element
* A arch-associated cranial nerve (cranial nerves V, VII, IX, X)
* An aortic arch artery

* **The arches** are separated externally by pharyngeal clefts (ectodermal) and internally by pharyngeal pouches (endodermal)
* **The first pharyngeal** cleft becomes the external acoustic meatus, and the remaining three clefts normally disappear.
* **The skeletal elements** of the PA are derived from midbrain or hindbrain neural crest, or from lateral plate mesoderm and occipital somites (PA mesoderm).

* **The paraxial mesoderm of PA** gives rise to a functionally related muscle group.
* **The muscles** that form in each arch are innervated by a cranial nerve branch
* **Each muscle** drags its nerve behind it as it migrates.

### Facial development

The basic facial morphology is created between the 4th and 10th weeks by development and fusions of five prominences (swellings or processes)

* An unpaired frontonasal process will form the forehead + temples + nose + philtrum of the upper lip + primary palate.
* A pair of maxillary processes will form the upper jaw.
* A pair of mandibular processes will form the lower jaw
* The maxillary and mandibular swellings derive from the first pharyngeal arch.
* The failure of an adequate fusion of some facial processes is responsible for facial defects called facial clefts

### Primary palate development

**Early 6th wk**

* the nasal placodes of the frontonasal prominence invaginate to form the nasal pits + the lateral (LNP) and medial nasal processes (MNP)

**6th wk**

* Contact of the MNPs with the maxillary processes (MaxP) (on each side) and later fusion of the LNP with the MNP

**Late 7th wk**

* Fusion of the MNP with each other after lateral and inferior expansion (form primordium of the nasal septum).
* Fusion of the MNP with the MaxP and formation of the intermaxillary process.

**Intermaxillary process**

* philtrum of the upper lip + upper jaw component (carries the 4 upper incisors ) + the primary palate.

### Secondary palate development

**8th-9th wk**

* Development of the palatine shelves (PS) from the medial walls of the MaxPs;
* Downward growth of the PS parallel to the lateral surface of the tongue.

**Late 9th wk**

* Rotation upward into a horizontal position and fusion of the PS with each other and with the primary palate (PP) to form the secondary palate (SP);

* The incisive foramen is the midline landmark between the PP and the SP.

### What is the fate of the medial epithelial seam upon palatal fusion?

Epithelial-mesenchymal transformation? No

Migration? Possible but no evidence

Apoptosis? Yes

### Anterior two-thirds of the tongue

The tongue develops from pharyngeal arches 1, 3 & 4 and from occipital somite mesoderm.

**Late 4th wk**

* Appearence of the tuberculum impar. (TI or median tongue bud) which derives from a median swelling of the first arch.)

**Early 5th wk**

* Distal tongue buds (or lateral lingual swellings) which overgrow the TI.

Expansion and growth of these swellings during embryonic and fetal life to form the anterior two thirds of the tongue.

### Posterior one-thrd of the tongue

**Late 4th wk**

* Appearence of the copula in the 2nd arch.

**5th and 6th wk**

* The hypopharyngeal eminence, derived from the 3rd and 4th arches, overgrows the copula and forms the posterior one-third of the tongue

* The terminal sulcus = boundary between the anterior 2/3 and posterior 1/3 of the tongue.
* The median sulcus = line of fusion between the right and left distal tongue buds.
* The foramen cecum = intersection of the MS and the TS.

### Muscles if the tongue

* All the muscles of the tongue (except the palatoglossus) are formed by mesoderm derived from the myotomes of the occipital somites.
* All the muscles (except the palatoglossus) are innervated by the hypoglossal nerve (cranial nerve XII).
* The palatoglossus is innervated by the pharyngeal branch of the vagus (nerve X).

### The mucosa of the tongue

* Derived from pharyngeal arch ecto- & endoderm.
* Innervated by sensory branches of the corresponding four cranial nerves.
* General sensory receptors (anterior 2/3) supplied by the lingual nerve (cranial nerve V3).
* The taste buds (anterior 2/3) are supplied by the chorda tympani (cranial nerve VII).
* The vallate papillae (terminal sulcus) and the general sensory endings of most of the 1/3 posterior mucosa are supplied by the glossopharyngeal nerve

### Craniofacial malformations (CFMs)

* Account for one third of all congenital defects.
* Have a multifactorial etiology.
* Genetic or induced.

**A number of teratogens are involved:**

* alcohol
* drugs such as hydantoin (anticonvulsive)
* Accutane
* toluene,
* cigarette smoking
* ionizing radiation
* hyperthermia

### Holoprosencephaly (HPE)

* Is a spectrum of anomalies ranging from mild to severe.
* Caused by disturbances in the early induction of the forebrain (prosencephalon).
* Depending on the severity of the condition, the frontonasal process, calvaria, midfacial structures and the forebrain can be deformed.
* Alcohol consumption during the 3rd wk is the most common cause of HPE.
* Mutations in the human Sonic hedgehog gene cause HPE (Roessler et al. 1996).
* Mice lacking Sonic hedgehog gene function display a phenotype reminiscent of HPE.

### Forebrain anomalies in HPE:

* defects of olfactory nerves, bulbs, tracts and associated structures
* (sometimes) defects of the corpus callosum.

**Typical facial anomalies in HPE:**

* a short, upturned nose
* a long upper lip without philtrum
* a highly arched palate
* retrognathia
* microcephaly (small skull)
* agenesis of the intermaxillary process (failure of the MNP to form)
* a single central upper incisor
* reduction or absence of other midfacial structures causes cebocephaly, hypotelorism (close-set eyes), or cyclopia.

### Holoprosencephaly and environmental factors

A common range plant - a corn lily - produces two chemicals

* jervine
* and cyclopamine

.... that inhibit Shh signaling.

**Other environmental factors:**

* maternal diabetes
* alcohol
* retinoic acid

### Other craniofacial syndromes

Involve defects of the FNP and a premature calvarial synostosis.

* The craniofrontonasal dysplasia syndrome: tall, narrow skull (acrocephaly) caused by a premature synostosis of the coronal suture + hypertelorism + nose and upper lip clefting.

**Apert, Pfeiffer and Crouzon syndromes: premature synostosis of cranial sutures.**

* Apert and Crouzon syndromes: Premature closure of the coronal suture.
* Pfeiffer syndrome: Premature closure of the coronal and sagittal sutures.

**FGFR mutations are associated with craniosynostosis and dwarfism**

* FGFR1 mutations ➝ Pfeiffer syndrome
* FGFR2 mutations ➝ Apert, Crouzon or Pfeiffer syndromes.
* FGFR3 mutations ➝ Crouzons or dwarfism syndromes

### Facial clefting defects

Result from complete or partial failure of fusion of the facial processes.

* Unilateral or bilateral cleft lip: failure of fusion of MaxP with the intermaxillary segment.
* Cleft palate: absence of fusion of palatal shelves with each other
* Cleft lip + cleft palate

**Clinical implications**

1. To understand the mechanisms behind:

a: aberrations in tooth number, shape and size.

b: toxic effects on tooth development.

c: genetic disturbances in tooth development.

d: odontogenic tumors and cysts.

2. Tooth development may also serve as an excellent model in the research of organogenesis and cell signaling in general.