Drosophila engrailed can substitute for mouse Engrailed1 function in mid-hindbrain, but not limb development.
The Engrailed-1 gene, En1, a murine homologue of the Drosophila homeobox gene engrailed (en), is required for midbrain and cerebellum development and dorsal/ventral patterning of the limbs. In Drosophila, en is involved in regulating a number of key patterning processes including segmentation of the epidermis. An important question is whether, during evolution, the biochemical properties of En proteins have been conserved, revealing a common underlying molecular mechanism to their diverse developmental activities. To address this question, we have replaced the coding sequences of En1 with Drosophila en. Mice expressing Drosophila en in place of En1 have a near complete rescue of the lethal En1 mutant brain defect and most skeletal abnormalities. In contrast, expression of Drosophila en in the embryonic limbs of En1 mutants does not lead to repression of Wnt7a in the embryonic ventral ectoderm or full rescue of the embryonic dorsal/ventral patterning defects. Furthermore, neither En2 nor en rescue the postnatal limb abnormalities that develop in rare En1 null mutants that survive. These studies demonstrate that the biochemical activity utilized in mouse to mediate brain development has been retained by Engrailed proteins across the phyla, and indicate that during evolution vertebrate En proteins have acquired two unique functions during embryonic and postnatal limb development and that only En1 can function postnatally.
Developmental Genetics Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine and Departments of Cell Biology and Physiology and Neuroscience, NYU Medical Center, New York, NY 10016, USA.
M C
MC
Hanks
C A
CA
Loomis
E
E
Harris
C X
CX
Tong
L
L
Anson-Cartwright
A
A
Auerbach
A
A
Joyner
D000818:Animals; D030801:Animals, Genetically Modified; D005075:Biological Evolution; D019521:Body Patterning; D004330:Drosophila; D029721:Drosophila Proteins; D005121:Extremities / Q000196:embryology*; D018390:Gene Targeting; D005816:Genetic Complementation Test; D018398:Homeodomain Proteins / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000196:embryology*; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins / Q000235:genetics; D012249:Rhombencephalon / Q000196:embryology*; D013045:Species Specificity; D013249:Sternum / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics; D000099266:Engrailed 2 Protein
D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000099266:Engrailed 2 Protein; C063459:En protein, Drosophila; C080330:En1 protein, mouse