[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Embryology](https://durgical.com/en/embryology/) › [Skeleton, muscles, limbs and skin](https://durgical.com/en/embryology/#a-musculoskeletal) › Limb development: the apical ectodermal ridge, ZPA and limb rotation

[Embryology](https://durgical.com/en/embryology/) · [Skeleton, muscles, limbs and skin](https://durgical.com/en/embryology/#a-musculoskeletal)

# Limb development: the apical ectodermal ridge, ZPA and limb rotation

- Process

Arms and legs sprout as buds at the end of the first month; three signalling centres decide their length, the order of the digits and which side is the palm.

Updated 2026-11-01

**See it in 3D:** [Humerus](https://durgical.com/en/anatomy/humerus/) · [Femur](https://durgical.com/en/anatomy/femur/) · [Radius](https://durgical.com/en/anatomy/radius/) · [Ulna](https://durgical.com/en/anatomy/ulna/) · [Tibia](https://durgical.com/en/anatomy/tibia/) · [Fibula](https://durgical.com/en/anatomy/fibula/) · [Scapula](https://durgical.com/en/anatomy/scapula/) · [Hip bone](https://durgical.com/en/anatomy/hip-bone/) · [1st metacarpal](https://durgical.com/en/anatomy/1st-metacarpal/) · [Proximal phalanx, thumb](https://durgical.com/en/anatomy/proximal-phalanx-of-the-thumb/)

## Key points

- Apical ectodermal ridge (FGF8) = proximodistal axis; lose it and the limb is truncated.
- ZPA (SHH) = anteroposterior axis; an extra anterior ZPA gives mirror-image digits.
- WNT7A (dorsal) and EN1 (ventral) = dorsoventral axis.
- Week 7: upper rotates 90° laterally, lower 90° medially.
- Syndactyly = failed interdigital apoptosis.
- Weeks 4 to 8 are the critical period: thalidomide then causes phocomelia.

## What it is

Limb buds appear at the end of week 4, the upper first and the lower one or two days later. Three signalling centres organise the three axes: the apical ectodermal ridge (proximodistal), the zone of polarizing activity (anteroposterior) and the dorsal and ventral ectoderm (dorsoventral). Digits separate by apoptosis, and in week 7 the limbs rotate in opposite directions. This is the window in which thalidomide acted.

## Key facts

- End of week 4: buds appear; the lower limb runs 1 to 2 days behind the upper.
- HOX genes set where they arise: upper limb opposite C5–T2, lower limb opposite L2–S2.
- Week 5: the apical ectodermal ridge (AER) forms on the distal rim of the bud.
- Week 6: hand and foot plates and the first cartilage models.
- Weeks 6 to 8: interdigital apoptosis separates the digits.
- Week 7: the upper limb rotates 90° laterally (thumb lateral, extensors posterior) and the lower limb 90° medially (big toe medial, extensors anterior).
- Week 12: primary ossification centres are present in all long bones.

## Step by step

- FGF10 from lateral plate mesoderm starts the bud at the level set by HOX genes.
- BMP from ventral ectoderm induces the apical ectodermal ridge on the distal rim.
- FGF8 and FGF4 from the ridge keep a zone of undifferentiated, dividing cells beneath it.
- Cells that leave the ridge's influence differentiate: arm or thigh first, then forearm or leg, finally hand or foot.
- SHH from the ZPA on the posterior border orders the digits; WNT7A and EN1 define back and palm.
- The ridge splits into five, and apoptosis between the digits separates them.
- Myoblasts from the somites invade the bud and form dorsal (extensor) and ventral (flexor) masses.
- Week 7: opposite rotation of the limbs; then endochondral ossification.

## Limb signalling centres

| Centre | Molecule | Axis | When lost |
| --- | --- | --- | --- |
| Lateral plate mesoderm | FGF10; TBX5 (arm), TBX4 (leg) | Bud initiation | No bud: amelia; TBX5: Holt–Oram |
| Apical ectodermal ridge | FGF8, FGF4 | Proximodistal | Truncated limb; the earlier, the shorter |
| Zone of polarizing activity (ZPA) | SHH | Anteroposterior (thumb to little finger) | Digits lost; extra anterior ZPA: mirror digits |
| Dorsal ectoderm | WNT7A → LMX1B | Dorsoventral (back) | Ventralised dorsum; LMX1B: nail–patella syndrome |
| Ventral ectoderm | EN1 (induced by BMP) | Dorsoventral (palm) | Palm takes on dorsal features |

## Markers

- FGF10
- FGF8
- FGF4
- SHH
- WNT7A
- LMX1B
- EN1
- TBX5
- TBX4
- HOX

## Clinical notes

- Thalidomide (weeks 4 to 6 of gestation): amelia and phocomelia.
- Holt–Oram (TBX5): thumb and radial anomalies with atrial or ventricular septal defects.
- HOXD13 mutations: synpolydactyly; HOXA13: hand–foot–genital syndrome.
- Rotation explains why lower-limb dermatomes spiral and why the knee bends the opposite way to the elbow.

## Memory aid

The ridge says 'how long', the zone says 'which finger', and the skin on top says 'which side is the back'.

## Test yourself

Think of the answer, then tap the question to see it.

## Which structure controls proximodistal limb growth, and with what signal?

The apical ectodermal ridge, through FGF8 and FGF4, which keep the underlying mesenchyme proliferating.

## What happens if ZPA tissue is grafted onto the anterior border of a limb bud?

A mirror-image duplication of the digits forms, because a second source of SHH now sits anteriorly.

## In which week do the limbs rotate, and in which direction?

In week 7: the upper limb rotates 90° laterally and the lower limb 90° medially.

## Which gene links upper-limb anomalies with heart defects in Holt–Oram syndrome?

TBX5, which takes part in upper-limb development and in septation of the heart.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/embryology/limb-development-the-apical-ectodermal-ridge-zpa-and-limb-rotation/)

## See it in 3D

The structures of Durgical's 3D anatomy where it is found.

- [Humerus](https://durgical.com/en/anatomy/humerus/)
- [Femur](https://durgical.com/en/anatomy/femur/)
- [Radius](https://durgical.com/en/anatomy/radius/)
- [Ulna](https://durgical.com/en/anatomy/ulna/)
- [Tibia](https://durgical.com/en/anatomy/tibia/)
- [Fibula](https://durgical.com/en/anatomy/fibula/)
- [Scapula](https://durgical.com/en/anatomy/scapula/)
- [Hip bone](https://durgical.com/en/anatomy/hip-bone/)
- [1st metacarpal](https://durgical.com/en/anatomy/1st-metacarpal/)
- [Proximal phalanx, thumb](https://durgical.com/en/anatomy/proximal-phalanx-of-the-thumb/)

## Related

- [Limb defects: amelia, meromelia, polydactyly and syndactyly](https://durgical.com/en/embryology/limb-defects-amelia-meromelia-polydactyly-and-syndactyly/)
- [Thalidomide and limb reduction defects](https://durgical.com/en/embryology/thalidomide-and-limb-reduction-defects/)
- [Muscles: somites, epaxial and hypaxial](https://durgical.com/en/embryology/muscles-somites-epaxial-and-hypaxial/)
- [Molecular regulation: Shh, Wnt, FGF, BMP, Hox genes and retinoic acid](https://durgical.com/en/embryology/molecular-regulation-shh-wnt-fgf-bmp-hox-genes-and-retinoic-acid/)
- [Paraxial mesoderm and somites: sclerotome, myotome, dermatome](https://durgical.com/en/embryology/paraxial-mesoderm-and-somites-sclerotome-myotome-dermatome/)
- [Clubfoot (talipes equinovarus)](https://durgical.com/en/embryology/clubfoot/)
- [Developmental dysplasia of the hip](https://durgical.com/en/embryology/developmental-dysplasia-of-the-hip/)

[← All of embryology](https://durgical.com/en/embryology/)

Educational content on embryonic development; not a guide to prenatal diagnosis or to medicines in pregnancy and no substitute for a health professional's advice. No doses are given.

Sources: [Holt-Oram syndrome: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/holt-oram-syndrome/) (MedlinePlus, US National Library of Medicine, 2026); [SHH gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/shh/) (MedlinePlus, US National Library of Medicine, 2026); [Limb Reduction Defects | Birth Defects | CDC](https://www.cdc.gov/birth-defects/about/limb-reduction-defects.html) (Centers for Disease Control and Prevention, 2026); Langman's Medical Embryology, 13th ed., ch. 12: Limbs (Wolters Kluwer, 2015).

## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake

Representative model, for educational purposes only.

---
Source: https://durgical.com/en/embryology/limb-development-the-apical-ectodermal-ridge-zpa-and-limb-rotation/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/embryology/limb-development-the-apical-ectodermal-ridge-zpa-and-limb-rotation/