UNSW Embryology
Musculoskeletal- Limb Development- Apical Ectodermal Ridge	Embryology Home Page
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Introduction 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? see molecular dev below). There is also a recent review on AER formation (More? Kimmel).
Molecular Development There is another page with an overview of Molecularar 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 Patterning- Axes Wing has been used as Model of limb development as chick wing easy to manipulate: removal, grafting, additional ARER, ZPA etc Limb Patterning- Axes Proximodistal Axis AER formed by Wnt7a (More? see factors- Wnt7a) then AER secretes FGF2, 4, 8 stimulates proliferation and outgrowth Dorsoventral Axis somite provides dorsal signal to mesenchyme which dorsalizes ectoderm ectoderm then signals back (Wnt7a) to mesenchyme to pattern limb Anteroposterior Axis ZPA zone of polarizing activity mesenchymal posterior region of limb addition of extra ZPA duplicated digits signal is Shh (More? see factors- SHH) Limb Axes Limb Patterning- Axes (More? see Limb Axes) Signals give positional information which is interpreted by Hox gene expression establishing programs of differentiation. (More? see factors- Hox) Proximodistal Axis Dorsoventral Axis Anteroposterior Axis
References Kimmel RA, Turnbull DH, Blanquet V, Wurst W, Loomis CA, Joyner AL [Related Articles] Two lineage boundaries coordinate vertebrate apical ectodermal ridge formation. Genes Dev 2000 Jun 1;14(11):1377-1389 recent review on the topic of how the AER is formed. Genes Dev Journal Link Loomis CA, Kimmel RA, Tong CX, Michaud J, Joyner AL. Analysis of the genetic pathway leading to formation of ectopic apical ectodermal ridges in mouse Engrailed-1 mutant limbs. Development. 1998 Mar;125(6):1137-48. Altabef M, Clarke JD, Tickle C. Dorso-ventral ectodermal compartments and origin of apical ectodermal ridge in developing chick limb. Development. 1997 Nov;124(22):4547-56. Altabef M, Logan C, Tickle C, Lumsden A. Engrailed-1 Misexpression in Chick Embryos Prevents Apical Ridge Formation but Preserves Segregation of Dorsal and Ventral Ectodermal Compartments. Dev Biol. 2000 Jun 15;222(2):307-316. Bell SM, Schreiner CM, Scott WJ. The loss of ventral ectoderm identity correlates with the inability to form an AER in the legless hindlimb bud. Mech Dev. 1998 Jun 1;74(1-2):41-50. Rodriguez-Esteban C, Schwabe JW, De La Pena J, Foys B, Eshelman B, Belmonte JC. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature. 1997 Mar 27;386(6623):360-6. Pizette S, Niswander L. BMPs negatively regulate structure and function of the limb apical ectodermal ridge. Development. 1999 Feb;126(5):883-94. Kosher RA, Savage MP, Chan SC. In vitro studies on the morphogenesis and differentiation of the mesoderm subjacent to the apical ectodermal ridge of the embryonic chick limb-bud. J Embryol Exp Morphol. 1979 Apr;50:75-97.
Terms anlage- (Ger. ) primordium, 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. dermatome- 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. dura mater- dystrophy- 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- fascia- fascicle- (=bundle) femur- 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. flexor- fossa- 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- 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- 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 cartilage- muscle- 3 main types of muscle (smooth, cardiac and skeletal) all derived from mesoderm but different regions. myotome- myoblast- 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. patella- 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. sclerotome- 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). somitic mesoderm- 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. tarsal- Tbx- T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification. tibia- 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). 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. zone of polarizing activity- (zpa) dorsal region with forming limbbud mesenchyme that secretes shh and regulates limb axis formation.
About Notes Notes from the Embryology Program compiled and written by Dr Mark Hill. Note Links to OMIM Entries are copies of originals for computers without internet access. Computers with internet access can directly access the database.	Links Serial Sections Homepage Human Homepage Pig Homepage Limb Development
m.hill@unsw.edu.au Date Last Modified: 20/6/2000 This site maintained by Dr M. Hill