Homeobox-containing genes are thought to have a role in controlling development. InDrosophila, theengrailed (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs,En1 andEn2, produced different developmental defects that frequently are lethal. The humanengrailed homologs1 and2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system and the limbs.[6]
Engrailed (En)1 is a homeobox gene that helps regulate development in the dorsal midbrain and anterior hindbrain (cerebellum andcolliculi) of humans. It is also essential in regulating the establishment of a dorso-ventral pattern in developing limbs. The expression ofEn1 is regulated until 13 days after fertilization by Fgf8, which controls the development of the forebrain and hindbrain.En1 is first expressed in this region on day 9.5 after fertilization for about 12 hours untilEn2 is expressed. AfterEn2 expression,En1 is expressed again in other tissues such as somites and limbectoderm throughout development.[7] Aknockout mouse model with theEn1 homeobox deleted was developed; mice died less than 24 hours after birth because appeared to be unable to feed. The brains of the mice were studied and most of the cerebellum, colliculi, and cranial nerves 3 and 4 were missing. There was clear deletion in the mid-hindbrain, isthmus, junction region that began at day 9.5 after fertilization. All of the mice demonstrated marked forepaw deformities including fusion of digits and abnormal dorso-ventral patterning. The 13th ribs and sternums displayed delayed and abnormalossification. The mouse model demonstrated that the expression ofEn1 is critical in the correct development of the brain, limbs, and sternum.[8]
In 2021, a group of scientists and physicians aroundAndrea Superti-Furga in Lausanne and Stefan Mundlos in Berlin showed that biallelic loss-of-function variants at theEN1 locus result in a human phenotype that includes a severe impairment of limb development as well as cerebellar aplasia,[9] reproducing the phenotype first observed in the gene knock-out mice described above. They also found that there is along non-coding RNA (lncRNA) element at approx. 300 kb distance fromEN1, that they calledMAENLI (for Master on Engrailed-1 in the Limbs), that is responsible for activation ofEN1 gene expression in the developing limbs. The biallelic loss of theMAENLI lncRNA element results in impairment of limb development in humans as seen in the EN1-associated condition, while cerebellar development is not affected.
^Wurst W, Auerbach AB, Joyner AL (July 1994). "Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum".Development.120 (7):2065–75.doi:10.1242/dev.120.7.2065.PMID7925010.
Logan C, Hanks MC, Noble-Topham S, Nallainathan D, Provart NJ, Joyner AL (1993). "Cloning and sequence comparison of the mouse, human, and chicken engrailed genes reveal potential functional domains and regulatory regions".Developmental Genetics.13 (5):345–58.doi:10.1002/dvg.1020130505.PMID1363401.
Logan C, Willard HF, Rommens JM, Joyner AL (February 1989). "Chromosomal localization of the human homeo box-containing genes, EN1 and EN2".Genomics.4 (2):206–9.doi:10.1016/0888-7543(89)90301-7.PMID2567700.
Joliot A, Trembleau A, Raposo G, Calvet S, Volovitch M, Prochiantz A (May 1997). "Association of Engrailed homeoproteins with vesicles presenting caveolae-like properties".Development.124 (10):1865–75.doi:10.1242/dev.124.10.1865.PMID9169834.
