Homeobox protein engrailed-1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''EN1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Function
Homeobox
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
-containing genes are thought to have a role in controlling development. In ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'', the ''engrailed'' (''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'' and ''En2'', produced different developmental defects that frequently are lethal. The human ''engrailed'' homologs ''1'' and ''2'' encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system and the limbs.
''Engrailed'' (''En'') ''1'' is a homeobox gene that helps regulate development in the dorsal midbrain and anterior hindbrain (
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
and
colliculi) of humans. It is also essential in regulating the establishment of a dorso-ventral pattern in developing limbs. The expression of ''En1'' 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 until ''En2'' is expressed. After ''En2'' expression, ''En1'' is expressed again in other tissues such as somites and limb
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...
throughout development.
A
knockout
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving strikin ...
mouse model with the ''En1'' 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 abnormal
ossification
Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in ...
. The mouse model demonstrated that the expression of ''En1'' is critical in the correct development of the brain, limbs, and sternum.
In 2021, a group of scientists and physicians around
Andrea Superti-Furga
Andrea Superti-Furga (born 1959 in Milan) is a Swiss-Italian pediatrician, geneticist and molecular biologist. He is the head of the Division of Genetic Medicine at the Lausanne University Hospital (CHUV) and a professor at the Faculty of Medicin ...
in Lausanne and Stefan Mundlos in Berlin showed that biallelic loss-of-function variants at the ''EN1'' locus result in a human phenotype that includes a severe impairment of limb development as well as cerebellar aplasia,
reproducing the phenotype first observed in the gene knock-out mice described above. They also found that there is a
long non-coding RNA (lncRNA) element at approx. 300 kb distance from ''EN1'', that they called ''MAENLI'' (for Master on Engrailed-1 in the Limbs), that is responsible for activation of ''EN1'' gene expression in the developing limbs. The biallelic loss of the ''MAENLI'' lncRNA element results in impairment of limb development in humans as seen in the EN1-associated condition, while cerebellar development is not affected.
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
External links
*
Transcription factors
{{gene-2-stub