Musculoskeletal System - Skull Development

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12 week fetal skull
Fetal Head (12 weeks) showing cartilage (blue) and bone (red)

The Skull is a unique skeletal structure in several ways: embryonic cellular origin (neural crest), form of ossification (intramembranous and endochondrial) and flexibility (fibrous sutures). The cranial vault (which encloses the brain) bones are formed by intramembranous ossification. While the bones that form the base of the skull are formed by endochondrial ossification.


  • endochondral - ethmoid, basi sphenoid, basi occipital, petrous temporal
  • intramembranous - facial skeleton (nasals, maxillae, premaxillae, zygomatic, mandible) and cranial vault (frontal, parietal, and squamous temporal)

The bones enclosing the brain have large flexible fibrous joints (sutures) which allow firstly the head to pass through the birth canal and secondly postnatal brain growth. (See also notes on Head Development) In humans, ossification within the skull continues postnatally, through puberty until mid 20's and in old age the sutures separating the vault plates are often completely ossified.

In the entire skeleton, early ossification occurs in the jaw and at the ends of long bones (More? see movie developing mouse). Osteoblasts manufacture bone and are derived from ectomesenchymal in origin. (More? see lineage below). Flexible fibrous sutures allow growth of the brain to be accomodated by calvarial plate growth. Recent studies have show that noggin (a BMP antagonist) is involved in closure of these sutures.

Developmentally and clinically there are several abnormalities associated with skull growth and palate development. These abnormalities can furthermore impact on other systems such as neural, sensory, respiratory and nutritional functions.

Category:Skull | Head Development | Palate Development | Temporomandibular Joint

Musculoskeletal Links: Introduction | Mesoderm | Somitogenesis | Limb | Cartilage | Bone | Bone Timeline | Axial Skeleton | Skull | Joint | Muscle | Muscle Timeline | Tendon | Diaphragm | Lecture - Musculoskeletal Development | Lecture Movie | Abnormalities | Limb Abnormalities | Cartilage Histology | Bone Histology | Skeletal Muscle Histology | Category:Musculoskeletal
Historic Musculoskeletal Embryology  
1902 - Pubo-femoral Region | Spinal Column and Back | Body Segmentation | Cranium | Body Wall, Ribs, and Sternum | Limbs | 1901 - Limbs | 1902 - Arm Development | 1906 Human Embryo Ossification | 1906 Lower limb Nerves and Muscle | 1907 - Muscular System | Skeleton and Limbs | 1908 Vertebra | 1909 Mandible | 1910 - Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | 1913 Clavicle | 1920 Clavicle | 1921 - External body form | Connective tissues and skeletal | Muscular | Diaphragm | 1929 Rat Somite | 1932 Pelvis | 1940 Synovial Joints | 1943 Human Embryonic, Fetal and Circumnatal Skeleton | 1947 Joints | 1949 Cartilage and Bone | 1957 Chondrification Hands and Feet | 1968 Knee
Historic Embryology
1910 Textbook Skull | 1910 Textbook Skull Images | 1910 30mm Embryo Skull | 1921 Human Brain Vascular | 1923 Head Subcutaneous Plexus | 1919 21mm Embryo Skull | 1920 Human Embryo Head Size | 1921 43 mm Fetal Skull | 1915 The Monotreme Skull | Historic Disclaimer

Some Recent Findings

Historic images of the skull by Vesalius
  • Transcriptional analysis of human cranial compartments with different embryonic origins[1] "Previous investigations suggest that the embryonic origins of the calvarial tissues (neural crest or mesoderm) may account for the molecular mechanisms underlying sutural development. The aim of this study was to evaluate the differences in the gene expression of human cranial tissues and assess the presence of an expression signature reflecting their embryonic origins. Of six paired comparisons, frontal and parietal compartments (distinct tissue types of calvaria, either bone or intrasutural mesenchyme) had the most different gene expression profiles despite being composed of the same tissue type (bone). Transcriptional profiles of two groups of tissues, frontal and metopic compartments vs. parietal and sagittal compartments, suggest differences in proliferation, differentiation and extracellular matrix production. Our data suggest that in the second trimester of human foetal development, a gene expression signature of neural crest origin still exists in frontal and metopic compartments while gene expression of parietal and sagittal compartments is more similar to mesoderm."
  • The BMP Ligand Gdf6 Prevents Differentiation of Coronal Suture Mesenchyme in Early Cranial Development[2] "Growth Differentiation Factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules. Previous studies have shown that Gdf6 plays a role in formation of a diverse subset of skeletal joints. In mice, loss of Gdf6 results in fusion of the coronal suture, the intramembranous joint that separates the frontal and parietal bones. .... Therefore, although BMPs are known to promote bone formation, Gdf6 plays an inhibitory role to prevent the osteogenic differentiation of the coronal suture mesenchyme."
  • Epigenetic control of skull morphogenesis by histone deacetylase 8[3] "Histone deacetylases (Hdacs) are transcriptional repressors with crucial roles in mammalian development. Here we provide evidence that Hdac8 specifically controls patterning of the skull by repressing a subset of transcription factors in cranial neural crest cells. Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells. Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1. These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase."
  • Expression of five frizzleds during zebrafish craniofacial development.[4] "Wnt/Planar Cell Polarity (PCP) signaling is critical for proper animal development. ...Frizzled (Fzd) homologues are Wnt receptors ...Closer examination revealed that fzd7b is expressed in the neural crest and the mesodermal core of the pharyngeal arches and in the chondrocytes of newly stacked craniofacial cartilage elements. However, fzd7a is only expressed in the neural crest of the pharyngeal arches and fzd8a is expressed in the pharyngeal endoderm."
  • Skull Abnormalities - Craniosynostosis[5] "Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, approximately 20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). ...These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment."
More recent papers
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Search term: Skull Embryology

Yuhei Ikeda, Satoshi Kokai, Takashi Ono A patient with mandibular deviation and 3 mandibular incisors treated with asymmetrically bent improved superelastic nickel-titanium alloy wires. Am J Orthod Dentofacial Orthop: 2018, 153(1);131-143 PubMed 29287639

Martin M Mortazavi, Syed A Quadri, Muhammad A Khan, Aaron Gustin, Sajid S Suriya, Tania Hassanzadeh, Kian M Fahimdanesh, Farzad H Adl, Salman A Fard, M Asif Taqi, Ian Armstrong, Bryn A Martin, R Shane Tubbs Subarachnoid Trabeculae: A comprehensive review of their embryology, histology, morphology and surgical significance. World Neurosurg: 2017; PubMed 29269062

Eleonoor A R Theunissen, Isabella C M Hoogslag, Erik van Spronsen, Roelof J Oostra, Fenna A Ebbens A unique anomaly of the ear: Oculo-auriculo-vertebral spectrum or an isolated disruption? Laryngoscope: 2017; PubMed 29243259

George E Kirtley The Aesthetic Zone Challenge. Dent Today: 2017, 36(6);74, 76-7 PubMed 29231671

Patrick D McGurk, Mary E Swartz, Jessica W Chen, Jenna L Galloway, Johann K Eberhart In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw. PLoS Genet.: 2017, 13(12);e1007112 PubMed 29227993

Fetal Skull

The Images below show the combined endochondral and intramembranous ossification that is occurring in early fetal development (week 12).

In the first 2 images the bone cartilage is shown in blue and the new bone in red.

Note the difference in appearance between the upper and lower jaw (maxilla and mandible), the currently cartilage base of the skull (chondrocranium) and the cranial vault (neurocranium).

Fetal head lateral.jpg

Fetal head lateral view

Fetal head medial.jpg

Fetal head medial view

Fetal head section 01.jpg

Fetal head section

This mid-line section through the fetal head shows features of the developing skull and the brain, face and mouth.
  • Neural
    • developing brain and brainstem.
    • lamina terminalis (site of anterior neuropore closure).
    • fourth ventricle.
    • developing pituitary sitting in the sella turcica.
  • Musculoskeletal
    • cartilage - septum of the nose.
    • bone - ossifying nasal concha.
    • bone - palate roof of mouth.
    • cartilage - soft palate back of mouth.
    • cartilage - base of skull and vertebra.
    • muscle - tongue, attached note foramen cecum.
    • bone - mandible.
    • cartilage - developing hyoid and thyroid bones.

Mandible Development

Meckel's cartilage

Meckel's cartilage, located within the first pharyngeal arch mandibular prominence, forms a cartilage "template" besides which the mandible develops by the process of intramembranous ossification. It is important to note that this cartilage template does not ossify (endochondral ossification) but provides a transient structure where the mandible will form, and later degenerates.

See also the 1957 historic paper on temporomandibular joint development.[6]

Embryonic and Fetal Mandible

Birth to Adult Mandible

Postnatal human mandible growth icon.jpg
 ‎‎Mandible Growth
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Postnatal human mandible growth 1.gif

Animated GIF

Mandible Development: Week 8 outer view | Week 8 inner view | Week 12 outer view | Week 12 inner view | Week 12 Head outer view | Week 12 Head inner view | Birth | Childhood | Adult | Old Age | Small Animation | Large Animation | Muscle Attachments | Mandible Ossification | 1909 Mandible | embryo 18 mm | embryo 24 mm | embryo 28 mm | fetus 43 mm | fetus 65 mm | fetus 55 mm | fetus 95 mm | human 18-24-95 mm | Skull Development | Head Development


Frontal bone

  • neural crest origin
  • requires Msx1 and Dlx5[7]

Parietal bone

  • paraxial mesoderm origin

Skull Views

Skull anterior.gif Skull superior.gif Skull lateral view.gif Bailey139.jpg
anterior view superior view lateral view lateral view
showing anterior fontenelle, sutures, mandible showing anterior fontenelle, sutures showing suture, mandible newborn skull

Skull Fontanels and Sutures

Adult Skull

The bones enclosing the brain have large flexible fibrous joints (sutures) which allow firstly the head to compress and pass through the birth canal and secondly to postnatally expand for brain growth. (More? Molecular Skull Sutures) These sutures gradually fuse at different times postnatally, firstly the metopic suture in infancy and the others much later. Abnormal fusion (synostosis) of any of the sutures will lead to a number of different skull defects, leading to disruption of brain development. (More? Abnormal Synostosis) In old age all these sutures are generally completely fused and ossified.

Skull Fontanels

The newborn skull has 6 fontanels (fontanelles) the most obvious are the anterior and posterior fontanels that close at different times postnatally.
  • posterior fontanel closes at about 3 months
  • anterior fontanel closes at about 18 months
Newborn Skull Fontanels

Newborn Skull Fontanels (CT, vertex view)

At the molecular level, accelerated suture intramembranous ossification can be mediated through a dual role of β-catenin in both the expansion of osteoprogenitors and the maturation of osteoblasts.[8] These researchers also show that disruption of Axin2/β-catenin signaling alters the regulation of the downstream transcription target, cyclin D1, in the canonical Wnt pathway.[9]

Computed Tomography Views

Skull CT normal sutures.jpg

Skull CT Vertex, later and basal views.[10]

Sutures and Fontanels

  • a - Metopic suture
  • b - coronal sutures
  • c - sagittal suture
  • d - lambdoid suture
  • e - squamosal suture
  • f - anterior fontanel
  • g - posterior fontanel
  • h - sphenoidal fontanel
  • i - mastoid fontanel

coronal suture

Skull CT normal sutures 01.jpg

lambdoid suture

Skull CT normal sutures 02.jpg

metopic suture begins at nose and runs superiorly to meet sagittal suture and fuses during infancy (fusion beginning at 3 months and completes by 6 to 8 months of age) before all other cranial sutures.

sagittal suture

Cranial Base Synchondroses

In the base of the skull there can also be found a number of synchondrosis, "cartilage sutures", that are the last to close and have a role in the ongoing growth of the postnatal skull. Synchondrosis is a type of cartilaginous joint in which the cartilage is usually converted into bone before adult life. It has been compared in appearance to a long bone growth plate, but is bipolar rather than unipolar in structure.

These sutures also lost at different times in postnatal development:

  • Inter-sphenoidal – around birth
  • Spheno-ethmoidal – 6-7 yrs
  • Spheno-occipital – 12-15 yrs

Fetal Head Growth

Fetal head growth circumference graph02.jpg Fetal head growth circumference graph01.jpg


There are several skull deformities caused by premature fusion (synostosis) of different developing skull sutures. Suture abnormalities are classified as either "simple" (only one suture involved) or "compound" (two or more sutures involved).

Oxycephalus (historic image from Hess, 1922)
* craniosynostosis premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation.
  • oxycephaly (tower skull) results from premature coronal suture synostosis.
  • plagiocephaly results from asymmetric coronal suture synostosis, incidence is approximately 1 in 300 live births.
  • lambdoid synostosis results from premature lambdoid suture synostosis, a rare abnormality (incidence is approximately 3 in 100,000 live births) which displaces ear posteriorly towards the fused suture.
  • caphocephaly results from premature sagittal suture synostosis.
  • trigoncephaly (wedge skull) results from metopic suture synostosis.

The CT images shown below are from a recent review of skull abnormalities.[10]


Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis.[11] "Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, approximately 20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). ...These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment."

Dolichocephaly and scaphocephaly

Skull CT abnormal 01.jpg
Dolichocephaly and scaphocephaly

(premature fusion of the sagittal suture)

Brachycephaly and anterior plagiocephaly

(Greek, brakhu = short) (Greek plagios = oblique)

  • brachycephaly - premature bicoronal fusion
  • anterior plagiocephaly - unicoronal fusion

Leads to a restriction of anterior-posterior calvarial growth and relatively unaffected biparietal growth.

Skull CT abnormal 02.jpg Skull CT abnormal 03.jpg

Skull Turricephaly

Skull CT abnormal 04.jpg

Skull Trigonocephaly

Skull CT abnormal 07.jpg

(Greek, trigonos = three angles) This abnormality results from the premature fusion of the metopic suture occurring before 6 months (3-9 months) of age.

Skull Oxycephaly

Skull CT abnormal 08.jpg

Images show oxycephaly from severe sagittal and coronal synostoses (arrowheads).

Craniofrontonasal Syndrome

Craniofrontonasal syndrome (CFNS) is a human X-linked developmental disorder caused by a mutation in ephrin-B1 affecting mainly females. Characterised by abnormal development of cranial and nasal bones, craniosynostosis (premature coronal suture fusion), and other extracranial anomalies (limb polydactyly and syndactyly).

Craniofrontonasal syndrome.jpg (a) Facial view showing marked hypertelorism, divergent squint, and central nasal groove (subject age, 1 year).

(b) Three-dimensional computed tomographic skull reconstruction (subject age, 8 months) showing right unicoronal synostosis, lateral displacement of orbits, and central defect between frontal bones. Note bony ridge at site of obliterated right coronal suture (arrowhead); the left coronal suture is patent (arrow). f, frontal bone; p, parietal bone.

(c) Longitudinal splitting of the nails is frequent.

Craniofrontonasal syndrome[12] Links: OMIM - Craniofrontonasal Syndrome

Skull Histology

A histological image of a skull bone formation by Intramembranous ossification.

Intramembranous ossification centre.jpg

Adult Skull

Adult Skull MRI Links: Skull Development - MRI
Adult Skull Movie 1 icon.jpg
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Adult Skull Movie 2 icon.jpg
 ‎‎Temporal Bones
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Adult Skull Movie 3 icon.jpg
 ‎‎Occipital - Frontal
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Adult Skull Movie 4 icon.jpg
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  1. Negar Homayounfar, Sarah S Park, Zahra Afsharinejad, Theodor K Bammler, James W MacDonald, Federico M Farin, Brigham H Mecham, Michael L Cunningham Transcriptional analysis of human cranial compartments with different embryonic origins. Arch. Oral Biol.: 2015, 60(9);1450-1460 PubMed 26188427
  2. Dawn E Clendenning, Douglas P Mortlock The BMP ligand Gdf6 prevents differentiation of coronal suture mesenchyme in early cranial development. PLoS ONE: 2012, 7(5);e36789 PubMed 22693558
  3. Michael Haberland, Mayssa H Mokalled, Rusty L Montgomery, Eric N Olson Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev.: 2009, 23(14);1625-30 PubMed 19605684
  4. Barbara E Sisson, Jacek Topczewski Expression of five frizzleds during zebrafish craniofacial development. Gene Expr. Patterns: 2009, 9(7);520-7 PubMed 19595791
  5. V P Eswarakumar, F Ozcan, E D Lew, J H Bae, F Tomé, C J Booth, D J Adams, I Lax, J Schlessinger Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc. Natl. Acad. Sci. U.S.A.: 2006, 103(49);18603-8 PubMed 17132737 | PNAS Link
  6. Moffatt BC. The prenatal development of the human temporomandibular joint. (1957) Carnegie Instn. Wash. Publ. 611, Contrib. Embryol., 36: .
  7. Il-Hyuk Chung, Jun Han, Junichi Iwata, Yang Chai Msx1 and Dlx5 function synergistically to regulate frontal bone development. Genesis: 2010, 48(11);645-55 PubMed 20824629
  8. Bo Liu, Hsiao-Man Ivy Yu, Wei Hsu Craniosynostosis caused by Axin2 deficiency is mediated through distinct functions of beta-catenin in proliferation and differentiation. Dev. Biol.: 2007, 301(1);298-308 PubMed 17113065
  9. Anthony J Mirando, Takamitsu Maruyama, Jiang Fu, Hsiao-Man Ivy Yu, Wei Hsu β-catenin/cyclin D1 mediated development of suture mesenchyme in calvarial morphogenesis. BMC Dev. Biol.: 2010, 10;116 PubMed 21108844
  10. 10.0 10.1 Paritosh C Khanna, Mahesh M Thapa, Ramesh S Iyer, Shashank S Prasad Pictorial essay: The many faces of craniosynostosis. Indian J Radiol Imaging: 2011, 21(1);49-56 PubMed 21431034 | PMC3056371 | Indian J Radiol Imaging.
  11. V P Eswarakumar, F Ozcan, E D Lew, J H Bae, F Tomé, C J Booth, D J Adams, I Lax, J Schlessinger Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc. Natl. Acad. Sci. U.S.A.: 2006, 103(49);18603-8 PubMed 17132737
  12. Stephen R F Twigg, Rui Kan, Christian Babbs, Elena G Bochukova, Stephen P Robertson, Steven A Wall, Gillian M Morriss-Kay, Andrew O M Wilkie Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc. Natl. Acad. Sci. U.S.A.: 2004, 101(23);8652-7 PubMed 15166289 | PNAS Link


M Shah, J S Ross, C VanDyke, R A Rudick, D E Goodkin, N Obuchowski, M T Modic Volume T1-weighted gradient echo MRI in multiple sclerosis patients. J Comput Assist Tomogr: 1992, 16(5);731-6 PubMed 1522265

E J Stelnicki, M P Mooney, H W Losken, J Zoldos, A M Burrows, R Kapucu, M I Siegel Ultrasonic prenatal diagnosis of coronal suture synostosis. J Craniofac Surg: 1997, 8(4);252-8; discussion 259-61 PubMed 9482048

R V Ocampo, J A Persing Sagittal synostosis. Clin Plast Surg: 1994, 21(4);563-74 PubMed 7813156

C A Vander Kolk, B S Carson Lambdoid synostosis. Clin Plast Surg: 1994, 21(4);575-84 PubMed 7813157

M M Cohen Sutural biology and the correlates of craniosynostosis. Am. J. Med. Genet.: 1993, 47(5);581-616 PubMed 8266985


Jeffrey Weinzweig, Richard E Kirschner, Alexander Farley, Philip Reiss, Jill Hunter, Linton A Whitaker, Scott P Bartlett Metopic synostosis: Defining the temporal sequence of normal suture fusion and differentiating it from synostosis on the basis of computed tomography images. Plast. Reconstr. Surg.: 2003, 112(5);1211-8 PubMed 14504503

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Additional Images

Historic Images

Historic Embryology

1910 Development of the Skeleton
1914 Human Fetus 40 mm Skull

Macklin CC. The skull of a human fetus of 40 mm 1. (1914) Amer. J Anat. 16(3): 317-386. Macklin CC. The skull of a human fetus of 40 mm 2. (1914) Amer. J Anat. 16(3): 387-426.

1921 43 mm Fetal Skull
1918 Gray's Anatomy


  • anterior fontanel - developing skull region that closes by about 20 months postnatally.
  • basion - anatomical region on the basiocciput located at the midpoint between the anterior margin and posterior margin (opisthion) of the foramen magnum.
  • compound craniosynostosis premature suture fusion involving two or more sutures.
  • craniosynostosis - (craniostenosis) the premature fusion of cranial sutures.
  • dermatocranium - (membranous) skull calvarial vault develops from intramembranous ossification.
  • harlequin eye - a term used to describe the prominent bilateral elliptical orbits of the skull seen in brachycephaly.
  • endochondral ossification - bone formation from a pre-existing cartilage template, such as the chondrocranium.
  • intramembranous ossification - bone formation from a membrane where no pre-existing cartilage is found, such as the calvarial vault component.
  • neurocranium - the portion of the skull that surrounds the brain. Ossification of bones in cranial base (endochondral) and vault (intramembranous).
  • opisthion - anatomical region located on the occipital bone, located at the midpoint of the posterior margin of the foramen magnum.
  • posterior fontanel - developing skull region that closes by about 3 months postnatally.
  • primary craniosynostosis - an intrinsic defect in a suture.
  • secondary craniosynostosis - premature closure of normal sutures due to systemic and metabolic (hyperthyroidism, hypercalcemia, hypophosphatasia, vitamin D deficiency, renal osteodystrophy, Hurler's Syndrome, sickle cell disease and thalassemia) and those that can affect brain growth.
  • simple craniosynostosis - premature fusion involving only one suture.
  • synostosis - premature fusion.
  • viscerocranium - facial skeleton and some anterior neck structures.

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Cite this page: Hill, M.A. 2018 Embryology Musculoskeletal System - Skull Development. Retrieved January 16, 2018, from

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