Download Limb Development: Hox Genes

Limb Development: Hox Genes
Lecture Outline
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Homeobox (Hox) Genes: Master Developmental Genes
Human HOX Genes
Homeobox Regulation of Gene Expression
Hox Gene Expression in the Mammalian Limb
Hox Gene Knockouts in Mice Lead to Limb Defects
Retinoic Acid: A Developmental Morphogen
Hox Genes: Mouse Knockout Mutants
HOX GENES: Mutation in Michigan Family
Cell Death & Digit Formation
Syndactyly in Humans
Homeobox (Hox) Genes: Master Developmental Genes
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1st identified in Drosophila (homeotic genes)--regulate development of body segments--bizarre
development when mutated
Homologous genes are present from Arthropods to Vertebrates (homeobox genes)
Highly conserved genes
Crucial to development
Functions still not well understood
Human HOX Genes
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39 Hox genes (i.e., they must be important) distributed in 4 linkage groups
Contain homeobox domain (highly conserved)
This domain gives them their name
Homeobox domain encodes a small protein called homeodomain protein segment
This protein binds DNA & regulates gene activity (i.e., transcription factor)
Genes are expressed in sequences that correlate with development of specific regions
Homeobox Regulation of Gene Expression
Hox Gene Expression in the Mammalian Limb
The HoxD gene complex is expressed in a specific pattern in the developing mouse forelimb. The pattern of
gene expression correlates with the linear arrangement of the genes in the genome. The following figure shows
a summary of the expression of the Hox genes relative to the final developed limb.
The next figure shows the pattern of expression of the HoxD genes in the developing limb. HoxD9 is expressed
earliest and continues throughout development. In contrast, HoxD13 is only expressed in the final stages of digit
formation. HoxD12-10 are expressed in decreasing amounts throughout limb development.
Hox Gene Knockouts in Mice Lead to Limb Defects
The patterns of Hox gene expression mediate specific events in limb development. The following figure shows
how knockouts of Hoxa11 or Hoxd11 lead to the loss of the radius and ulna from the mouse forelimb.
Retinoic Acid: A Developmental Morphogen
Retinoic acid (RA) is the active form of Vitamin A and has many developmental functions (Review: Kastner et
al, 1985. Cell 83: 859-869). Excess RA and vitamin A deficiency each affect left-right symmetry (for example,
for normal formation of the mammalian heart) through alterations in gene expression (Chauzaud et al, 1999.
Development 126: 2589-2596). For an excellent review of the development of the vertebrate heart see Fishman
and Chien, 1997. Development 124: 2099-2117. While retinoic acid has specific effects on limb development,
the general concensus is that it is not a true morphogen in the development of the mammalian limb. For more
info on retinoic acid, see the supplementary material on the chick limb.
Hox Genes: Mouse Knockout Mutants
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Targeted mutation KO'd Hox13 gene
Abnormalities in limbs and also in genitals.
HOX GENES: Mutation in Michigan Family
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Defects: thumbs and toes
Women: uterine abnormalites & sterility
Examine DNA: Mutation present in HOXA13
Thus, HOXA13 gene important for development (Dickman, 1997. Science 245: 1568)
Cell Death & Digit Formation
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Some humans are born with webbed fingers
Webs removed just after birth
In normal development: Cell Death (Apoptosis) Occurs between Digits
Large amount of lysosomal enzyme activity
Syndactyly in Humans
Syndactyly = Webbed (fused) Digits: Due to lack of Cell Death (apoptosis)
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