Musculoskeletal System - Limb Development

Embryology - 24 Apr 2024        Expand to Translate
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Introduction

Human embryonic limb development (week 6)

Human embryonic limb development (week 8)

Appendicular skeleton

Limb bud geometry and patterning

The early "limb bud" consists of a simple ectoderm cover with a mesoderm core that vascularises and both somite mesoderm and nerves invade. Generally the upper limb develops before the lower limb, and in the case of birds and bats then develops as a wing. Externally the structure of the limb is established by the end of the embryonic period (week 8), except for nails and hair. Internally limb tissue differentiation (bone, muscle) continues through the fetal period and into postnatal development.

Limb development has been studied in the embryo extensively as a model for how pattern formation is established. For example, in the chicken the early limb bud was modified and transplanted to identify key signalling regions. Then beads coated with specific factors were used and finally genetic modification of animal models. Note that pattern formation signals differ from those required for overt tissue differentiation.

The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. The musculoskeletal system consists of skeletal muscle, bone, and cartilage and is mainly mesoderm in origin with some neural crest contribution.

Somites appear bilaterally as pairs at the same time and form earliest at the cranial (rostral,brain) end of the neural groove and add sequentially at the caudal end. This addition occurs so regularly that embryos are staged according to the number of somites that are present. Different regions of the somite differentiate into dermomyotome (dermal and muscle component) and sclerotome (forms vertebral column). An example of a specialized musculoskeletal structure can be seen in the development of the limbs.

Skeletal muscle forms by fusion of mononucleated myoblasts to form mutinucleated myotubes. Bone is formed through a lengthy process involving ossification of a cartilage formed from mesenchyme. Two main forms of ossification occur in different bones, intramembranous (eg skull) and endochondrial (eg limb long bones) ossification. Ossification continues postnatally, through puberty until mid 20s. Early ossification occurs at the ends of long bones.

Musculoskeletal abnormalities and limb abnormalities are one of the largest groups of congenital abnormalities.

Development of the other parts of the appendicular skeleton, shoulder and pelvis, are described on separate pages.

| Shoulder Development | Pelvis Development

Some Recent Findings

Digits and fin rays share common developmental histories "Here, we provide a functional analysis, using CRISPR/Cas9 and fate mapping, of 5' hox genes and enhancers in zebrafish that are indispensable for the development of the wrists and digits of tetrapods. We show that cells marked by the activity of an autopodial hoxa13 enhancer exclusively form elements of the fin fold, including the osteoblasts of the dermal rays. In hox13 knockout fish, we find that a marked reduction and loss of fin rays is associated with an increased number of endochondral distal radials. These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates." AER Evolution - A somitic contribution to the apical ectodermal ridge is essential for fin formation "The transition from fins to limbs was an important terrestrial adaptation, but how this crucial evolutionary shift arose developmentally is unknown. Current models focus on the distinct roles of the apical ectodermal ridge (AER) and the signaling molecules that it secretes during limb and fin outgrowth. In contrast to the limb AER, the AER of the fin rapidly transitions into the apical fold and in the process shuts off AER-derived signals that stimulate proliferation of the precursors of the appendicular skeleton. ...Here we show that invasion by cells of a newly identified somite-derived lineage into the AER in zebrafish regulates apical fold induction. Ablation of these cells inhibits apical fold formation, prolongs AER activity and increases the amount of fin bud mesenchyme, suggesting that these cells could provide the timing mechanism proposed in Thorogood's clock model of the fin-to-limb transition." Review - Xenopus Limb bud morphogenesis "Xenopus laevis, the South African clawed frog, is a well-established model organism for the study of developmental biology and regeneration due to its many advantages for both classical and molecular studies of patterning and morphogenesis. While contemporary studies of limb development tend to focus on models developed from the study of chicken and mouse embryos, there are also many classical studies of limb development in frogs. These include both fate and specification maps, that, due to their age, are perhaps not as widely known or cited as they should be. This has led to some inevitable misinterpretations- for example, it is often said that Xenopus limb buds have no apical ectodermal ridge, a morphological signalling centre located at the distal dorsal/ventral epithelial boundary and known to regulate limb bud outgrowth. These studies are valuable both from an evolutionary perspective, because amphibians diverged early from the amniote lineage, and from a developmental perspective, as amphibian limbs are capable of regeneration. Here, we describe Xenopus limb morphogenesis with reference to both classical and molecular studies, to create a clearer picture of what we know, and what is still mysterious, about this process." Frog Development Engrailed 1 mediates correct formation of limb innervation through two distinct mechanisms "Engrailed-1 (En1) is expressed in the ventral ectoderm of the developing limb where it plays an instructive role in the dorsal-ventral patterning of the forelimb. Besides its well-described role as a transcription factor in regulating gene expression through its DNA-binding domain, En1 may also be secreted to form an extracellular gradient, and directly impact on the formation of the retinotectal map. We show here that absence of En1 causes mispatterning of the forelimb and thus defects in the dorsal-ventral pathfinding choice of motor axons in vivo. In addition, En1 but not En2 also has a direct and specific repulsive effect on motor axons of the lateral aspect of the lateral motor column (LMC) but not on medial LMC projections. Moreover, an ectopic dorsal source of En1 pushes lateral LMC axons to the ventral limb in vivo. Thus, En1 controls the establishment of limb innervation through two distinct molecular mechanisms." Review - How the embryo makes a limb: determination, polarity and identity "The vertebrate limb with its complex anatomy develops from a small bud of undifferentiated mesoderm cells encased in ectoderm. The bud has its own intrinsic polarity and can develop autonomously into a limb without reference to the rest of the embryo. In this review, recent advances are integrated with classical embryology, carried out mainly in chick embryos, to present an overview of how the embryo makes a limb bud. We will focus on how mesoderm cells in precise locations in the embryo become determined to form a limb and express the key transcription factors Tbx4 (leg/hindlimb) or Tbx5 (wing/forelimb)." Developmental Dynamics - Special Issue: Special Issue on Limb Development May 2011 Volume 240, Issue 5

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Limb Embryology <pubmed limit=5>Limb Embryology</pubmed> Search term: Limb Development <pubmed limit=5>Limb Development</pubmed>

Older papers

Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb "Multipotent Pax3-positive (Pax3(+)) cells in the somites give rise to skeletal muscle and to cells of the vasculature. We had previously proposed that this cell-fate choice depends on the equilibrium between Pax3 and Foxc2 expression. In this study, we report that the Notch pathway promotes vascular versus skeletal muscle cell fates. ...We now demonstrate that in addition to the inhibitory role of Notch signaling on skeletal muscle cell differentiation, the Notch pathway affects the Pax3:Foxc2 balance and promotes the endothelial versus myogenic cell fate, before migration to the limb, in multipotent Pax3(+) cells in the somite of the mouse embryo." Muscle Development | Notch GATA6 Is a Crucial Regulator of Shh in the Limb Bud "In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the "Zone of Polarizing Activity", an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient." Sonic hedgehog Transient downregulation of Bmp signalling induces extra limbs in vertebrates "Bone morphogenetic protein (Bmp) signalling has been implicated in setting up dorsoventral patterning of the vertebrate limb and in its outgrowth. Here, we present evidence that Bmp signalling or, more precisely, its inhibition also plays a role in limb and fin bud initiation. Temporary inhibition of Bmp signalling either by overexpression of noggin or using a synthetic Bmp inhibitor is sufficient to induce extra limbs in the Xenopus tadpole or exogenous fins in the Danio rerio embryo, respectively. We further show that Bmp signalling acts in parallel with retinoic acid signalling, possibly by inhibiting the known limb-inducing gene wnt2ba." Global gene expression analysis of murine limb development "Here we describe the global gene expression dynamics during early murine limb development, when cartilage, tendons, muscle, joints, vasculature and nerves are specified and the musculoskeletal system of limbs is established. We used whole-genome microarrays to identify genes with differential expression at 5 stages of limb development (E9.5 to 13.5), during fore- and hind-limb patterning." Spatially Controlled Cell Proliferation in Limb Bud Morphogenesis"Our data run contrary to the proliferation gradient hypothesis, indicating instead that oriented cell behaviours are important for driving elongation." Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development "One such event is antero-posterior (AP) polarization of early limb buds and activation of morphogenetic Sonic Hedgehog (SHH) signaling in the posterior mesenchyme, which in turn promotes outgrowth and specifies the pentadactylous autopod. Inactivation of the Hand2 transcriptional regulator from the onset of mouse forelimb bud development disrupts establishment of posterior identity and Shh expression, which results in a skeletal phenotype identical to Shh deficient limb buds. ... Our study uncovers essential components of the transcriptional machinery and key interactions that set-up limb bud asymmetry upstream of establishing the SHH signaling limb bud organizer." The apical ectodermal ridge (AER) can be re-induced by wounding "First, we assessed the sequence of events following limb amputation in chick embryos and compared the features of limb development and regeneration in amphibians and chicks. Based on our findings, we attempted to re-induce the AER. When wnt-2b/fgf-10-expressing cells were inserted concurrently with wounding, successful re-induction of the AER occurred."

Textbooks

Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders. Development of Limbs Skeletal System Muscular System The Developing Human: Clinically Oriented Embryology (10th edn)  UNSW Students have online access to the current 10th edn. through the UNSW Library subscription (with student Zpass log-in). APA Citation: Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders. Links: PermaLink | UNSW Embryology Textbooks | Embryology Textbooks | UNSW Library Introduction to the Developing Human First Week of Human Development Second Week of Human Development Third Week of Human Development Fourth to Eighth Weeks of Human Development Fetal Period Placenta and Fetal Membranes Body Cavities and Diaphragm Pharyngeal Apparatus, Face, and Neck Respiratory System Alimentary System Urogenital System Cardiovascular System Skeletal System Muscular System Development of Limbs Nervous System Development of Eyes and Ears Integumentary System Human Birth Defects Common Signaling Pathways Used During Development Appendix : Discussion of Clinically Oriented Problems

Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R., Francis-West, P.H. & Philippa H. (2015). Larsen's human embryology (5th ed.). New York; Edinburgh: Churchill Livingstone. UNSW Library subscription Chapter 18 - Development of the Limbs (chapter links only work with a UNSW connection). Essentials of Human Embryology Larson Chapter 11 p207-228

Objectives

Comparison of mammalian limbs

Mouse limb (E14.5)

• Identify the components of a somite and the adult derivatives of each component.
• Give examples of sites of (a) endochondral and (b) intramembranous ossification and to compare these two processes.
• Identify the general times (a) of formation of primary and (b) of formation of secondary ossification centres, and (c) of fusion of such centres with each other.
• Briefly summarise the development of the limbs.
• Describe the developmental abnormalities responsible for the following malformations: selected growth plate disorders; congenital dislocation of the hip; scoliosis; arthrogryposis; and limb reduction deformities.

Development Overview

Below is a very brief overview using simple figures of 3 aspects of early musculoskeletal development. More detailed overviews are shown on other notes pages Mesoderm and Somite, Vertebral Column, Limb in combination with serial sections and Carnegie images.

Mesoderm Development

	Cells migrate through the primitive streak to form mesodermal layer. Extraembryonic mesoderm lies adjacent to the trilaminar embryo totally enclosing the amnion, yolk sac and forming the connecting stalk.
	Paraxial mesoderm accumulates under the neural plate with thinner mesoderm laterally. This forms 2 thickened streaks running the length of the embryonic disc along the rostrocaudal axis. In humans, during the 3rd week, this mesoderm begins to segment. The neural plate folds to form a neural groove and folds.
	Segmentation of the paraxial mesoderm into somites continues caudally at 1 somite/90minutes and a cavity (intraembryonic coelom) forms in the lateral plate mesoderm separating somatic and splanchnic mesoderm. Note intraembryonic coelomic cavity communicates with extraembryonic coelom through portals (holes) initially on lateral margin of embryonic disc.
	Somites continue to form. The neural groove fuses dorsally to form a tube at the level of the 4th somite and "zips up cranially and caudally and the neural crest migrates into the mesoderm.

Somite Development

	Mesoderm beside the notochord (axial mesoderm, blue) thickens, forming the paraxial mesoderm as a pair of strips along the rostro-caudal axis.
	Paraxial mesoderm towards the rostral end, begins to segment forming the first somite. Somites are then sequentially added caudally. The somitocoel, is a cavity forming in early somites, which is lost as the somite matures.
	Cells in the somite differentiate medially to form the sclerotome (forms vertebral column) and dorsolaterally to form the dermomyotome.
	The dermomyotome then forms the dermotome (forms dermis) and myotome (forms muscle). Neural crest cells migrate beside and through somite.
	The myotome differentiates to form 2 components dorsally the epimere and ventrally the hypomere, which in turn form epaxial and hypaxial muscles respectively. The bulk of the trunk and limb muscle coming from the Hypaxial mesoderm. Different structures will be contributed depending upon the somite level. Limb skeletal muscle arises from the hypomere region of the myotomes adjacent to the developing upper (C5-C8) and lower (L3-L5) limb buds.

Limb Axis Formation

Limb bud geometry and patterning

Four Concepts - much of the work has been carried out using the chicken and more recently the mouse model of development.

1. Limb Initiation
2. Proximodistal Axis
3. Dorsoventral Axis
4. Anteroposterior Axis

Mouse limb Patterning Images

Mouse Limb Images: Tbx3 and Tbx2 forelimb E10 | Alx3 and Gli3 forelimb E10 | Fgf and Hox forelimb E10.5 | Bmp4 forelimb E11.5 | Bmp4 hindlimb E11.5 | Shh forelimb E11.5 | Fgf8 hindlimb E11.5 | Sox9 forelimb E12.5 | Msx2 forelimb E12.5 | Shh hindlimb E12.5

Links: Fgf | Hox | Shh | Sox | Limb Development | Mouse Development

Limb Initiation

• Fibroblast growth factor (FGF) coated beads can induce additional limb
• FGF10 , FGF8 (lateral plate intermediate mesoderm) prior to bud formation
• FGF8 (limb ectoderm) FGFR2
• FGF can respecify Hox gene expression (Hox9- limb position)
• Hox could then activate FGF expression

Note that during the embryonic period there is a rostrocaudal (anterior posterior) timing difference between the upper and lower limb development

• this means that developmental changes in the upper limb can precede similar changes in the lower limb (2-5 day difference in timing)

Limb Identity

Forelimb and hindlimb (mouse) identity appears to be regulated by T-box (Tbx) genes, which are a family of transcription factors.

• hindlimb Tbx4 is expressed.
• forelimb Tbx5 is expressed.
• Tbx2 and Tbx3 are expressed in both limbs.

Related Research - PMID: 12490567 | Development 2003 Figures | Scanning electron micrographs of E9 Limb bud wild-type and Tbx5del/del A model for early stages of limb bud growth | PMID: 12736217 | Development 2003 Figures

Tbx3 and Tbx2 expression in E9.75 to 10.5 wild-type mouse embryonic forelimb.

Body Axes

• Anteroposterior - (Rostrocaudal, Craniocaudal, Cephalocaudal) from the head end to opposite end of body or tail.
• Dorsoventral - from the spinal column (back) to belly (front).
• Proximodistal - from the tip of an appendage (distal) to where it joins the body (proximal).

Proximodistal Axis

Limb proximodistal developmental regions

Mouse limb (E14.5)

• Apical Ectodermal Ridge (AER) formed by Wnt7a
• then AER secretes FGF2, 4, 8
• stimulates proliferation and outgrowth

The developing limb can be described along the proximodistal axis as having three main regions:

1. Stylopod - the proximal region the limb, the skeletal component of the upper limb (forelimb) is the humerus, and for the lower limb (hindlimb) is the femur.
2. Zeugopod - the mid-section of the limb , the skeletal components of the upper limb (forelimb) are the radius and ulna, and for the lower limb (hindlimb) are the tibia and fibula.
3. Autopod - the distal region the limb, the musculoskeletal component of the upper limb (forelimb) is the hands, and for the lower limb (hindlimb) is the foot.

Dorsoventral Axis

• Somites - provides dorsal signal to mesenchyme which dorsalizes ectoderm
• Ectoderm - then in turn signals back (Wnt7a) to mesenchyme to pattern limb

Wnt7a

• name was derived from 'wingless' and 'int’
• Wnt gene first defined as a protooncogene, int1
• Humans have at least 4 Wnt genes
• Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein
• patterning switch with different roles in different tissues
• mechanism of Wnt and receptor distribution still being determined (free diffusion, restricted diffusion and active transport)

One WNT receptor is Frizzled (FZD)

• Frizzled gene family encodes a 7 transmembrane receptor

Fibroblast growth factors (FGF)

• Family of at least 17 secreted proteins
• bind membrane tyrosine kinase receptors
• Patterning switch with many different roles in different tissues
• FGF8 = androgen-induced growth factor, AIGF

FGF receptors

• comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4) similar protein structure
  • 3 immunoglobulin-like domains in extracellular region
  • single membrane spanning segment
  • cytoplasmic tyrosine kinase domain

Anteroposterior Axis

Shh expression in ZPA mouse forelimb (E11.5)

• Zone of polarizing activity (ZPA)
• a mesenchymal posterior region of limb
• secretes sonic hedgehog (SHH)
  • note digit 1 (thumb/big toe) is the only digit that forms independent of SHH activity.
• apical ectodermal ridge (AER), which has a role in patterning the structures that form within the limb
• majority of cell division (mitosis) occurs just deep to AER in a region known as the progress zone
• A second 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

Hindlimb Tbx2 model

• HAND2 - upstream of SHH controls expression of genes in the proximal limb bud.
  • anterior/posterior polarity of limb bud mesenchyme (affecting Gli3 and Tbx3 expression).
• TBX3 - required downstream of HAND2 to refine posterior Gli3 expression boundary.

Week 5

Carnegie stage 13	Carnegie stage 14	Carnegie stage 15

Links: Week 5 | Carnegie stage 13 | Carnegie stage 14 | Carnegie stage 15

Week 6

Digital rays become visible on the upper limb.

Links: Week 6 | Carnegie stage 16 | Carnegie stage 17

Week 7

Carnegie stage 18	Carnegie stage 19

Digital rays become visible on the lower limb.

Links: Week 7 | Carnegie stage 18 | Carnegie stage 19

Week 8

Links: Week 8 | Carnegie stage 20 | Carnegie stage 21 | Carnegie stage 22 | Carnegie stage 23

Limb Rotation

Human Embryo (stage 19) showing direction of limb rotation.

Interdigital Apoptosis

Interdigital apoptosis in the mous hindlimb.

Early development of both the hand and foot appear initially as "paddles" at the end of the upper and lower limb respectively. As they continue to grow the digits (fingers and toes) are initially "webbed" together and the cells in the webbing die by programmed cell death to form the separate digits, this process is described as interdigital apoptosis.

Interdigital apoptosis, like general limb growth, occurs first in the upper limb and then later in the lower limb.

Links: Apoptosis

Fetal Growth

Fetal limb X-ray

Embryonic period - the external appearance of both the upper and lower limb has been formed. Fetal period - the limbs continue to grow significantly in length (elongate).  ‎‎Fetal Development Page | Play Play the associated animation to observe the relative change in limb dimensions. Links: Fetal Development

Limb Vessels

Lower Limb

These figures by Senior are from an historic 1919 study.

• Lower Limb (1919)
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  6 mm embryo

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  8.5 mm embryo

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  12 mm embryo

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  14 mm embryo

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  17.6 mm embryo

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  18 mm embryo

• ==Limb Bone==
• In addition, there are two quite separate aspects to this development.
• ==Shoulder and Pelvis==
• The skeletal shoulder consists of: the clavicle (collarbone), the scapula (shoulder blade), and the humerus. Development of his region occurs through both forms of ossification processes.
• ==Limb Skeletal Muscle==
• Embryonic skeletal muscles arise from the somite myotome region giving rise to myogenic progenitor cells.
• * limb level somites - cells from the hypaxial (ventrolateral) lips of the dermomyotome delaminate and migrate into the limb bud to form the musculature of the limbs.
• * between the limbs somites - cells delaminate from the edges or lips of the epithelial dermomyotome to form the subjacent postmitotic myotome, which gives rise to trunk muscles.
• ===Myogenesis===
• * Early myogenic progenitor cells in the dermomyotome can be initially identified by the transcription factor Pax3.
• * Subsequent myogenic program development then depends on the myogenic determination factors (Myf5, MyoD, and MRF4), both Myf5 and MyoD are expressed in the limbs.
• * Final differentiation of these cells into post-mitotic muscle fibers in the limb bud is regulated by another myogenic determination factor, Myogenin.
• ==Wing as Limb Model==
• * chicken wing easy to manipulate
• ** removal, addition and rotation of limb regions
• ** grafting additional AER, ZPA
• ** implanting growth factor secreting structures
• ==Mouse Limb Model==
• Fore-limb and hind-limb buds for stages E9.5 to E13.5. Hindlimbs are morphologically delayed by about half a day.
• * Light blue - indicate mesenchymal condensations.
• * Thick black lines - indicate cartilage as determined by alcian blue staining.
• ===Forelimb===
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  Tbx5

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  Fbxo41

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  Hoxc5

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  Hoxb5

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  Prdm1

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  Hoxb6

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  Etv2

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  Egr1

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  Figf

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  Sp6

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  Cited1

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  Prox1

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  SmarcD2

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  Echdc1

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  Sim2

Mouse forelimb cartilage and bone (E14.5 E18.5)

Hindlimb

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  Mouse E12.5 Hoxa

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  Tbx4

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  Ptx1

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  Hoxc10

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  Hoxc9

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  Dmrt2

Links: Mouse Development

Bat Limb Model

Images of the bat embryo Miniopterus schreibersii fuliginosus at embryonic Stages 13-17.

(aer - apical ectodermal ridge; chp - chiropatagium; eb - elbow; kn - knee)

Links: Bat Limb Development | Bat Development

Molecular

Fibroblast Growth Factors

• Fgf8 - morphogen gradient forms by a source-sink mechanism with freely diffusing molecules.

Bone Morphogenetic Protein

• Bmp2, Bmp4 and Bmp7 - co-required in the mouse AER for normal digit patterning but not limb outgrowth

Links: Bone Morphogenetic Protein

Hand2

The HAND2 gene encodes a basic helix-loop-helix (bHLH).

Links: Fibroblast Growth Factor | Sonic hedgehog | Wnt | Hand2 | OMIM

References

Reviews

<pubmed>26249743</pubmed> <pubmed>23827682</pubmed> <pubmed>18341703</pubmed> <pubmed>17661738</pubmed>

Articles

<pubmed>20347761</pubmed> <pubmed>20386744</pubmed> <pubmed>19207183</pubmed> <pubmed>11693301</pubmed>

Search PubMed

Search April 2010

• Limb Development - All (776) Review (108) Free Full Text (196)
• apical ectodermal ridge - All (95) Review (2) Free Full Text (31)
• zone polarizing activity - All (15) Review (2) Free Full Text (7)

Search Pubmed: Limb Development | apical ectodermal ridge | zone polarizing activity | limb bud skeletal muscle

Additional Images

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  Adult appendicular skeleton

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  Mouse limb development

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  Mouse forelimb bud Tbx3 and Tbx2

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  Mouse forelimb bud Shh expression and BMP pathway

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  Mouse forelimb bud Fgf4, Hoxd13 and Hoxa13

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  Mouse hindlimb buds Shh expression

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  Bmp4 forelimb E11.5

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  Bmp4 hindlimb E11.5

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  Shh forelimb E11.5

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  Fgf8 hindlimb E11.5

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  Sox9 forelimb E12.5

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  Msx2 forelimb E12.5

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  Shh hindlimb E12.5

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  Mouse hindlimb buds Fgf8 expression

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  Mouse hindlimb buds Bmp4 expression

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  Limb 3D map of cell proliferation rates

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  Limb changing 3D geometry

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  Limb mesenchymal cell shape

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  Bone structure

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  Endochondral bone

Historic Images

Limb Images: 274-278 Spinal Column and Lower Limb | 279-284 Lower Limb | 285-288 Knee | 289 Os Coxae | 290 Femur | 291 Tibia | 292 Fibula | 293 Foot | 294 | 295 | 296 | 297 | 298-299 | 300 Forearm and Hand | 301 Upper Limb Joints | 302 Clavicle | Upper Limb Ossification 1 | Upper Limb Ossification 2 | Bone Development Timeline

Skeleton and Connective Tissues: Connective Tissue Histogenesis | Skeletal Morphogenesis | Chorda Dorsalis | Vertebral Column and Thorax | Limb Skeleton | Skull Hyoid Bone Larynx

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  274-278

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  279-284

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  285-288

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  289

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  Bone Ossification Inferior Extremity

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  Bone Ossification Inferior Extremity

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  294-297

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  Table-Skeleton

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  Table- Bone Ossification Superior Extremity

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  Table- Bone Ossification Superior Extremity

Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold. Chapter 20. The Limbs

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  Fig. 233. Lateral view of a human embryo at the 28th day, showing the Limb Buds, Lateral Edges, and Primitive Segments.

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  Fig. 234. Development of the Upper Limb.

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  Fig. 235. Development of the Lower Limb.

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  Fig. 236. The Corresponding Points {A, B, C, and D) in the Ilium and Scapula.

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  Fig. 237. Section of the Arm Bud of a human embryo at the end of the 4th week.

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  Fig. 238. Schematic Section showing the Origin and Arrangement of the Muscles and Nerves of the Limbs.

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  Fig. 239. The Distribution of the Posterior Roots of the Spinal Nerves on the Flexor Aspect of the Arm.

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  Fig. 240. Diagram to show the typical Manner in which the Posterior Nerve Roots are distributed in the Lower Limb.

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  Fig. 241. Flexor Aspect of the Lower Limb showing the Sensory Distribution of the Segmental or Spinal nerves.

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  Fig. 242. Diagram of the Pelvic Girdle of a Lizard.

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  Fig. 243. The Pelvic Girdle of a Human Foetus at the 5th week.

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  Fig. 244. The Shoulder Girdle of Ornithorynchus.

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  Fig. 245. The Parts in the Shoulder Girdle of a human foetus which correspond with those of Ornithorynehus.

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  Fig. 246. The Carpal Bones of a Tortoise.

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  Fig. 247. The Os Trigenum and Bones of the Tarsus

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  Fig. 248. The Foetal and Adult (in dotted outline) Forma of the Astralagus contrasted.

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  Fig. 249. Latissimo-condyloideus Muscle.

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  Fig. 250. The Morphology of the Short Muscles of the Digits.

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  Fig. 251. Showing the Origin of the Ligamentum Teres and Reflected Bundle of the Capsular Ligament.

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  Fig. 252. Showing the Origin of the Crucial Ligaments of the Knee.

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Cite this page: Hill, M.A. (2024, April 24) Embryology Musculoskeletal System - Limb Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Musculoskeletal_System_-_Limb_Development

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G