and Molecular Mechanisms in Development

Figure 14-16 General transcription factors, shown in blue, and RNA polymerase bind to cis-acting sequences closely adjacent to the messenger RNA (mRNA) transcriptional start site; these cis-acting sequences are collectively referred to as the promoter. More distal enhancer or silencer elements bind specialized and tissue-specific transcription factors. Coactivator proteins facilitate a biochemical interaction between specialized and general transcription factors. See Sources & Acknowledgments.

The importance of transcription factors in normal development is illustrated by an unusual mutation of HOXD13 that causes synpolydactyly, an incompletely dominant condition in which heterozygotes have interphalangeal webbing and extra digits in their hands and feet. Rare homozygotes have similar but more severe abnormalities and also have bone malformations of the hands, wrists, feet, and ankles (Fig. 14-17). The HOXD13 mutation responsible for synpolydactyly is caused by expansion of a polyalanine tract in the amino-terminal domain of the protein; the normal protein contains 15 alanines, whereas the mutant protein contains 22 to 24 alanines. The polyalanine expansion that causes synpolydactyly is likely to act by a gain-of-function mechanism (see Chapter 11), as heterozygosity for a HOXD13 loss-of-function mutation has only a mild effect on limb development, characterized by a rudimentary extra digit between the first and second metatarsals and between the fourth and fifth metatarsals of the feet. Regardless of the exact mechanism, this condition demonstrates that a general function for HOX genes is to determine regional identity along specific body axes during development.


Figure 14-17 An unusual gain-of-function mutation in HOXD13 creates an abnormal protein with a dominant negative effect. Photographs and radiographs show the synpolydactyly phenotype. A and B, Hand and radiograph of an individual heterozygous for a HOXD13 mutation. Note the branching metacarpal III and the resulting extra digit IIIa. The syndactyly between digits has been partially corrected by surgical separation of III and IIIa-IV. C and D, Hand and radiograph of an individual homozygous for a HOXD13 mutation. Note syndactyly of digits III, IV, and V and their single knuckle; the transformation of metacarpals I, II, III, and V to short carpal-like bones (stars); two additional carpal bones (asterisks); and short second phalanges. The radius, ulna, and proximal carpal bones appear normal. E and F, Foot and radiograph of the same homozygous individual. Note the relatively normal size of metatarsal I, the small size of metatarsal II, and the replacement of metatarsals III, IV, and V with a single tarsal-like bone (stars). See Sources & Acknowledgments.

Morphogens and Cell to Cell Signaling

One of the best examples of a developmental morphogen is hedgehog, originally discovered in Drosophila and named for its ability to alter the orientation of epidermal bristles. Diffusion of the hedgehog protein creates a gradient in which different concentrations of the protein cause surrounding cells to assume different fates. In humans, several genes closely related to Drosophila hedgehog also encode developmental morphogens; one example is the gene sonic hedgehog (SHH). Although the specific programs controlled by hedgehog in Drosophila are very different from those controlled by its mammalian counterparts, the underlying themes and molecular mechanisms are similar. For example, secretion of the SHH protein by the notochord and the floor plate of the developing neural tube generates a gradient that induces and organizes the different types of cells and tissues in the developing brain and spinal cord (Fig. 14-18A). SHH is also produced by a small group of cells in the limb bud to create what is known as the zone of polarizing activity, which is responsible for establishing the posterior side of the developing limb bud and the asymmetrical pattern of digits within individual limbs (see Fig. 14-18B).


Figure 14-18 A, Transverse section of the developing neural tube. Sonic hedgehog protein released from the notochord diffuses upward to the ventral portion of the developing neural tube (brown); high concentrations immediately above the notochord induce the floor plate, whereas lower concentrations more laterally induce motor neurons. Ectoderm above (dorsal to) the neural tube releases bone morphogenetic proteins that help induce neural crest development at the dorsal edge of the closing neural tube (dark purple). B, Morphogenetic action of the sonic hedgehog (SHH) protein during limb bud formation. SHH is released from the zone of polarizing activity (labeled polarizing region in B) in the posterior limb bud to produce a gradient (shown with its highest levels as 4, declining to 2). Mutations or transplantation experiments that create an ectopic polarizing region in the anterior limb bud cause a duplication of posterior limb elements. See Sources & Acknowledgments.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on and Molecular Mechanisms in Development
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