Somites form and then begin to differentiate forming sclerotome, dermomyotome and then dermatome and myotome. The lateral portion of the myotome edge migrates at level of limbs (upper limb first then lower) and mixes with somatic mesoderm. Meanwhile the dermotome continues to contribute cells to myotome.
Limb development occurs at different times for forelimbs and hindlimbs. In the mid-4th week, human upper limb buds first form and lower limbs about 2 days later. The limbs form at vertebra segmental levels C5-C8 (upper limbs) L3-L5 (lower limbs).
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Upper Limb (Stage 23) |
Changes in External Appearance of Upper Limb (embryonic stages, not to scale. More? Upper Limb Movie) |
Page Links: Introduction | Some Recent Findings | Appendicular Skeleton | Limb Axes | Hands and Feet | Limb Ossification | Molecular Development | Carnegie Stage - Upper Limb | Limb Movies | Somite Development | Limb Development Abnormalities | References | Glossary
Other Pages: Stage 13/14 Limbbuds | Stage 22 | Stage 22 Upper Limb | Stage 22 Lower Limb
Ten Berge D, Brugmann SA, Helms JA, Nusse R. Wnt and FGF signals interact to coordinate growth with cell fate specification during limb development. Development. 2008 Oct;135(19):3247-57.
"We have identified target genes that are synergistically regulated by Wnts and FGFs, and show how these factors actively suppress differentiation and promote growth. Finally, we show how the spatial restriction of Wnt and FGF signals to the limb ectoderm, and to a specialized region of it, the apical ectodermal ridge, controls the distribution of cell behaviors within the growing limb, and guides the proper spatial organization of the differentiating tissues."
Sun M, Ma F, Zeng X, Liu Q, Zhao XL, Wu FX, Wu GP, Zhang ZF, Gu B, Zhao YF, Tian SH, Lin B, Kong XY, Zhang XL, Yang W, Lo W, Zhang X. Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long-range, limb-specific SHH enhancer. J Med Genet. 2008 Apr 16;
Nissim S, Allard P, Bandyopadhyay A, Harfe BD, Tabin CJ. Characterization of a novel ectodermal signaling center regulating Tbx2 and Shh in the vertebrate limb. Dev Biol. 2007 Apr 1;304(1):9-21
"The data presented here identify the non-AER border of dorsal-ventral ectoderm as a new signaling center in limb development that localizes the ZPA to the limb margin. This finding explains the tight restriction of Shh expression to the posterior margin throughout limb outgrowth as well as the tight restriction of Shh expression to the anterior margin in many mutants exhibiting preaxial polydactyly."
Nissim S, Hasso SM, Fallon JF, Tabin CJ. Regulation of Gremlin expression in the posterior limb bud. Dev Biol. 2006 Nov 1;299(1):12-21. (More? OMIM - Gremlin)
"Proper outgrowth of the limb bud requires a positive feedback loop between Sonic hedgehog (Shh) in the zone of polarizing activity (ZPA) and Fgfs in the overlying apical ectodermal ridge. The Bmp antagonist Gremlin is expressed in a domain anterior to the ZPA and is thought to act as a signaling intermediate between Shh and Fgf."
The appendicular skeleton consists of: Shoulder girdle, Upper limb (arm, hand), Pelvic girdle, Lower limb (leg, foot).
The limb is initially mesenchyme with an ectodermal covering. Within this mesenchyme blood vessels begin forming, the largest (marginal vein) is adjacent to the tip of the limbbud.
At the tip of the limbbud lies a thickened ridge of ectoderm, the apical ectodermal ridge (AER), which has a role in patterning the structures that form within the limb. The majority of cell division (mitosis) occurs just deep to AER and this region is known as the progress zone. Another region at the base of the limbbud beside the body, the zone of polarizing activity (ZPA) has a similar patterning role to the AER, but in determining another axis of the limb. (More? Molecular Development).
In the 5th week hand and footplates appear at the ends of limb buds and ridges form digital rays. Cells between the digital rays are removed by programmed cell death (apoptosis).
Late in Carnegie stage embryogenesis (Stage 20-23, 8th week) limb rotation occurs. Forelimbs and hindlimbs rotate in different directions, upper limb rotates dorsally, lower limb rotates ventrally, thumb and toe rostral, knee and elbow face outward.
Bones within the limb form by endochondrial ossification (begins Carnegie stage 18) throughout embryo. This process is the replacement of cartilage with bone (week 5-12).
For more information see Bone Development
There is another page with an overview of Molecular Development of Musculoskeletal structures and for more specific information about factors involved in limb patterning look at the Molecular Development Page or use the links below.
Limb Initiation
Limb Specification (Fore- Hind-)
Limb Patterning- Axes
Limb Patterning- Axes
Below are links to movies generated from the above Carnegie images. Note that the series of movie images are not to scale as the early images would be far too small to see any detail.
Arm Movie Page or Movie on new page (179Kb)
Limb Abnormalities both genetic and environmentally derived and now covered in more detail on a page Limb Abnormalities).
Nissim S, Allard P, Bandyopadhyay A, Harfe BD, Tabin CJ. Characterization of a novel ectodermal signaling center regulating Tbx2 and Shh in the vertebrate limb. Dev Biol. 2006 Dec 9;
McKee PR, et al. [See Related Articles] Skeletal relationships in the human embryonic foot based on three-dimensional reconstructions. Acta Anat (Basel). 1987;129(1):34-42.
Search PubMed: Feb 2007 "limb bud development" 1,264 reference articles of which 132 were reviews.
Search PubMed Now: limb bud development | limb development | musculoskeletal development
(More? PubMed- Medline)
Selected Lists of References from PubMed March 1999 search results are available for Department of Anatomy computers without internet access: Somite Reviews | Somitogenesis Abstracts | Mesoderm Review List
Computers with internet access can search from either Below or directly from PubMed Internet Access
A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Old Glossary
anlage - (German, anlage = primordium) a structure or cells which will form a future structure.
apical ectodermal ridge- (=AER) specialized region of ectoderm at the tip of the growing limbbuds that specifies proximo/distal axss of limb development
aponeurosis- thin flat sheet tendon.
apoptosis - the process of programmed cell death. In development of the limbs occurs in the "paddle" if both the hand and foot, generating the separated digits. Occurs in many tissues of the embryo and adult.
axillary fossa - the future "armpit" region
brachial plexus - mixed spinal nerves innervating the upper limb form a complex meshwork (crossing).
cartilage - connective tissue from mesoderm in the embryo forms initial skeleton replaced by bone. In adult, found on surface of bone joints.
carpal - the term used to describe the bones of upper limb wrist region.
dermomyotome - dorsolateral half of each somite that forms the dermis and muscle.
dorsal root ganglia- (=spinal ganglia) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
ectoderm - the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.
ectodermal ring - the thickened ring of ectoderm seen dorsally in the early (stage13/14) embryo adjacent to the dermatome. Ectoderm ventrally is relatively thin, gaining its dermatome component at a later stage.
endochondrial ossification - the process of replacement of the cartilagenous framework by osteoblasts with bone.
epaxial myotome - the dorsal portion of the myotome that generates dorsal skeletal muscles (epaxial muscles).
extracellular matrix - material secreted by and surrounding cells. Consists if fibers and ground substance.
extensor - term for a muscle which opens or straightens a joint or limb.
fascia - (Latin, fascia = "band") connective tissue layer, superficial and deep.
fascicle - (=bundle) term used to describe a bundle, muscle fibers or nerves etc.
femur - (Latin, femur = "thigh" bone) the single lower limb bone lying between the knee and pelvis.
fibroblast growth factors - (FGF) a family of at least 10 secreted proteins that bind membrane tyrosine kinase receptors. A patterning switch with many different roles in different tissues. (FGF8 = androgen-induced growth factor (AIGF)
fibroblast growth factor receptor - receptors comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4). They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain.
fibula - (calf bone) smaller of the two lower limb bones below the knee.
flexor - term for a muscle which closes or bends a joint or limb.
growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)
hox - (=homeobox) family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.
humerus - the single upper limb bone lying between the shoulder and elbow.
hypaxial myotome - the ventral portion of the myotome that generates ventral skeletal muscles (hypaxial muscles).
inguinal fossa - the region of the lower limb ajacent to flexor surface (exuivilant to the axillary fossa of the upper limb).
lumbar plexus- mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).
mesenchyme - embryonic connective tissue cellular organisation.
mesoderm- the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.
metacarpal - the term used to describe the bones of upper limb hand region between wrist (carpus) and the bones of the fingers (phalanges).
muscle - there are 3 main types of muscle (smooth, cardiac and skeletal) all derived from mesoderm but different regions.
myoblas t- the undifferentiated mononucleated muscle cells that will fuse together to form a multinucleated myotube, then mature into a muscle fibre.
MyoD - transcription factor involved in the determination of muscle cells in the somite. A basic helix-loop-helix factor which binds DNA.
myotome - the portion of the dermamyotome that generates skeletal muscle. Has 2 components epaxial (dorsal muscles ) hypaxial (ventral muscles).
neural crest - cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Those that remain on the dorsal neural tube form the sensory spinal ganglia (DRG). Neural crest cells migrate into the somites.
Pax - name derived from Drosophila gene "paired" (prd) the "paired box" is a amino end 124 amino-acid conserved domain (signature aa 35-51: P-C-x(11)-C-V-S). Transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, nine member proteins from Pax-1 to Pax-9. Regulate differentiation of many different tissues. Some members of the family (PAX3, PAX4, PAX6, PAX7) also contain a functional homeobox domain.
radius - (Latin, radius = "ray") larger of the two upper limb bones below the elbow.
sclerotome - the ventromedial half of each somite that forms the vertebral body and intervertebral disc.
segmentation - to break a solid structure into a number of usually equal size pieces.
spinal nerve - mixed nerve (motor and sensory) arising as lateral pairs at each vertebral segmental level.
somatic mesoderm - derived from lateral mesoderm closest to the ectoderm and separated from other component of lateral mesoderm (splanchnic, near endoderm) by the intraembryonic coelom.
somite- segmental block (ball) of mesoderm formed from paraxial mesoderm adjacent to notochord (axial mesoderm). Differentiates to form initially sclerotome and dermamyotome (then dermotome and myotome).
somitocoel - a transient cavity that appears within each of the the early forming somites then is lost.
somitogenesis - the process of segmentation of the paraxial mesoderm to form "mesoderm balls" beginning cranially (humans day20) and extending caudally at 1 somite/90 minutes until approx. 44 pairs have been formed.
sonic hedgehog - (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the Limb it is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.
syndactyly - fusion of digits.
tarsus - bones in the foot between the tibia and fibula and the metatarsus.
Tbx - T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification.
tibia - (shinbone) larger of the two lower limb bones below the knee.
transcription factor- a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2).
ulna - (elbow bone) smaller of the two upper limb bones below the elbow.
Wnt7a- The designation 'Wnt' was derived from 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. At least one WNT receptor is Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.
wrist - anatomical region of upper limb, the skeleton of which is formed from the carpal bones.
zone of polarizing activity- (ZPA) A limb region, dorsally located within the developing limbbud mesenchyme that secretes shh and regulates limb axis formation.
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New 2010 Site
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This page is an overview of Limb development covering a few key issues on pattern formation and mesoderm development with links to additional resources.
Limb development requires a study of several systems, a coordinated establishment of pattern (molecular) on mainly mesodermal components which also have a covering ectoderm (skin) and invading neural (sensory, motor, neural crest) components.
There is additional page covering Limb Development Abnormalities
Please email Dr Mark Hill if you wish to make a comment about this current project.
