Limb bud

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Limb bud
Details
Precursorlateral plate mesoderm
Identifiers
Latingemmae membrorum
MeSHD018878
TEbud_by_E5.0.3.0.0.0.5 E5.0.3.0.0.0.5
Anatomical terminology

The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development.[1] In the development of the human embryo the upper limb bud appears in the third week and the lower limb bud appears four days later.[2]

The limb bud consists of undifferentiated mesoderm cells that are sheathed in ectoderm.

muscles.[3]

The limb bud remains active throughout much of limb development as it stimulates the creation and

Shh signals.[6] Additionally, though not known as a specific signaling region like AER and ZPA, the dorsal-ventral axis is established in the limb bud by the competitive Wnt7a and BMP signals that the dorsal ectoderm and ventral ectoderm use respectively.[7][8] Because all of these signaling systems reciprocally sustain each other's activity, limb development is essentially autonomous after these signaling regions have been established.[3]

Position and formation

The Hox genes, which define features along the anterior-posterior axis of a developing organism, determine at which points along the axis that limb buds will form.[9] Though limbs emerge at different locations in different species, their positions always correlate with the level of Hox gene expression along the anterior-posterior axis.[9] All limb buds must also rely on other signaling factors to obtain their forelimb or hindlimb identity; Hox gene expression influences expression of T-box proteins that, in turn, determine limb identity for certain organisms.[3]

In turn, the activation of T-box protein activates signaling cascades that involve the

FGF8 secreted by the AER acts to keep the cells of the limb mesenchyme in a mitotically active state and sustains their production of FGF10.[12] positive feedback loop between the limb mesenchymal cells and the AER maintains the continued growth and development of the entire limb.[13]

In addition to limb outgrowth, the formation of a crucial signaling center, the

FGF8 secretion – to ensure proper mitotic activity of the limb bud mesenchyme beneath.[3]

In chickens,

Tbx5 appear to be important specifically for limb outgrowth in mice.[14]

Relationship between hox gene expression and limb patterning

Within the limb bud, expression of specific

Hox genes play in limb development was found when researchers effected Hox gene expressions in zebrafish by adding retinoic acid during gastrulation; This experiment resulted in a duplication of limbs.[16] Although excess retinoic acid can alter limb patterning by ectopically activating Shh expression, genetic studies in mouse that eliminate retinoic acid synthesis have shown that RA is not required for limb patterning.[17]

Chicken development is a wonderful example of this specificity of Hox gene expression in regard to limb development. The most 3’ Hoxc genes (HOXC4, HOXC5) are expressed only in the anterior limbs in chickens, while the more 5’ genes (HOXC9, HOXC10, HOXC11) are expressed only in the posterior limbs.[9] The intermediate genes (HOXC6, HOXC8) are expressed in both the upper and lower limbs in chickens.[9]

As previously stated, limb development is essentially autonomous after the signaling centers (AER) and

Shh signals initiate and regulate Hox gene expression in the developing limb bud.[18]
Though many of the finer details remain to be resolved, a number of significant connections between Hox gene expression and the impact on limb development have been discovered.

The pattern of

autopod.[19]

Relevant experiments

FGF10 can induce limb formation, but T-box proteins, Pitx1, and Hox genes determine identity [1]

By mimicking the initial FGF10 secretions of the lateral plate mesoderm cells, limb development can be initiated. Other signaling molecules are implicated in determining the limb's identity.

  1. Placement of FGF10-containing beads beneath chick ectodermal cells results in the formation a limb bud, AER,
    Tbx4
    expression. When beads were placed in the middle of the flank tissue, the anterior portion expressed Tbx5 and forelimb features, while the posterior portion of the limb expressed Tbx4 and hindlimb features.
  2. When chick embryos were engineered to constitutively express
    Tbx4 (via viral-transfection) throughout their flank tissue, every limb they grew was a leg, even those that formed in the anterior region, which would normally become wings. This confirms the role of T-box proteins
    in the type of limb that develops.
  3. Knocking out
    Tbx5 knockout prevents FGF10
    expression in the lateral plate mesoderm in mice.
  4. The Hox pathway affects Tbx expression, which in turn affects FGF10 expression.[3]
  5. When
    Tbx4
    —plays a role in the emergence of hindlimb properties.
HOXD11 expression correlates with Shh signals secretion[20]

HOXD11 is expressed posteriorly, near the ZPA, where the highest levels of

Shh signal
expression occur.

  1. When
    Shh signaling
    is stimulated, HOXD11 expression follows.
Cutaneous innervation of the right upper extremity.
Mesenchymal cells determine limb identity, but the AER maintains limb outgrowth through FGF signal secretion[1]

These experiments reveal that the limb mesenchyme contains the necessary information concerning limb identity, but the AER is needed to stimulate the mesenchyme to live up to its destiny (of becoming an arm, leg, etc.)

  1. When the AER is removed, limb development halts. If an FGF-bead is added in the AER's place, normal limb development proceeds.
  2. When an extra AER is added, two limbs form.
  3. When forelimb mesenchyme is replaced with hindlimb mesenchyme, a hindlimb grows.
  4. When forelimb mesenchyme is replaced with non-limb mesenchyme, the AER regresses, and limb development halts.
ZPA's role in establishing polarity and further limb development[21]

The ZPA first specifies anterior-posterior polarity (and dictates digit identity), and then, by sustaining AER activity, it ensures that the necessary cell proliferation occurs for normal formation of a five-digit limb.

  1. When Shh signals normally secreted from the
    Shh
    downregulation during limb bud expansion, the number of digits was decreased, but the identities of the formed digits was not altered.

Relevant genes and proteins

Associated molecules include:[1]

  • FGF8
    secretion.
  • FGF8
    .
  • FGF8
    expression.
  • BMP
    activity, FGF expression in the AER is maintained.
  • Tbx5
    is activated by another Pitx1-like messenger, is unknown.
  • Tbx4 is one of its downstream targets. Pitx1 and Tbx4 encode transcription factors that are expressed throughout the developing hindlimb but not forelimb buds. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphological characteristics of hindlimbs.[22]
  • Pitx1
    ) proteins. Determines where limb buds will form, and what limbs will develop there.

References

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