Embryology · Skeleton, muscles, limbs and skin

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 · Femur · Radius · Ulna · Tibia · Fibula · Scapula · Hip bone · 1st metacarpal · Proximal phalanx, thumb

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.

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.

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See it in 3D

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

← All of 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 (MedlinePlus, US National Library of Medicine, 2026); SHH gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Limb Reduction Defects | Birth Defects | CDC (Centers for Disease Control and Prevention, 2026); Langman's Medical Embryology, 13th ed., ch. 12: Limbs (Wolters Kluwer, 2015).

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Representative model, for educational purposes only.