Foundations of Human Development: Impact of Hox Genes on Human Embryonic Development 

Hox genes are primarily known for encoding very essential transcription factors that aide in the developmental process of many species by regulating the expression of other genes. Hox genes are known for giving positional information to surrounding cells. They direct particular cells to produce specific structures depending on their position within the body. Hox genes were first discovered and studied in Drosophila, where they seemed to be accountable for establishing segment identity. Thus, if a Hox gene is knocked out in Drosophila, the part of the body affected by the misexpression will develop into another. Hox genes have also been found in mammals, including humans. For every single Hox gene expressed in Drosophila, humans express four copies of the same Hox gene complex. Hox genes are expressed throughout human embryonic development and their misexpression has caused many human developmental malformations.

The overall shape that a human embryo takes on is because of the expression of Hox genes. In fact, in humans Hox genes control the orientation and structure of the vertebra and spinal cord. They are also in charge of making sure limb development is occurring in the correct location. There is a total of 39 Hox genes found in vertebrates, which can be divided into 4 separate groups called A, B, C, and D. In mammals these groups are located on different chromosomes: 7p15, 17q21.2, 12q13, and 2q3. They are found in the neural tube, neural crest, paraxial mesoderm, and surface ectoderm.

Early in development, Hox genes are arranged spatially in such a way that the genes at one end of a chromosome (3’) are expressed more at the head end (anterior) of the embryo than the genes (5’) at the tail end (posterior). For example, Hox5 is expressed in the last cervical vertebrae while Hox6 is expressed in the first thoracic vertebrae. This phenomenon is called temporal collinearity and it occurs during patterning of the anterior-posterior axis of the body, proximal-distal axis, and the anterior-posterior axis of limbs and appendages. Temporal collinearity plays an important role in embryogenesis. During embryogenesis cells have to become committed to turning into a certain tissue. They require positional information in order to commit to differentiating into the correct tissue. So, along the anterior-posterior axis there is a sequence of differing Hox gene expression which determines the type of vertebrae that is formed. This lets the cells know what type of tissue they have to differentiate into.

Hox genes are also essential in limb bud development in human embryo. They divide the limb bud into five different sections along the anterior-posterior axis.

Clusters A and D are particularly responsible for the positional regulation of appendages: fingers and toes. They are very important in the development of the anterior-posterior axis.

It has been found that mutations in 10 Hox genes cause human malformations and disorders: HOXA1, HOXA2, HOXA11, HOXA13, HOXB1, HOXB13, HOXC13, HOXD4, HOXD10, and HOXD13.

Bosely-Salih-Alorainy syndrome is characterized by “sensorineural hearing loss, inner ear abnormalities, delayed motor milestones, and internal carotid artery malformations”.4 Some inner ear abnormalities include “cavity deformity, absence of cochlea, semicircular canals or vestibule”.4 Some individuals with Bosely-Salih-Alorainy syndrome have reported an occurrence of cardiovascular malformations such as a ventricular septal defect and an interrupted aortic arch. Some facial dysmorphisms can be identified as low-set ears, flattened ear helices, and bony facial asymmetry. This syndrome is caused by a homozygous mutation that occurs in the HOXA1 gene. Mutations in the HOX1A are also responsible for Athabascan brainstem dysgenesis syndrome (ABDS), which is more severe than its counterpart. People that have this syndrome have “horizontal gaze palsy, profound sensorineural hearing loss, severe intellectual disability, facial and bulbar weakness, central hypoventilation, and conotruncal cardiac malformation”.4

HOXA2 mutations are responsible for autosomal recessive microtia. Microtia is a congenital deformity that results in an abnormally shaped ear. In fact, microtia can be so severe that the entire ear may be nonexistent.5 Individuals with this mutation experience “grade II microtia, a short and narrowed auditory canal, cleft palate, and occasionally unilateral facial paresis”.4 They also appear to experience severe hearing impairment, but heterozygous carriers seem to have normal hearing and anatomy.

HOXA11 mutations cause thrombocytopenia and radioulnar synostosis. Thrombocytopenia is a condition in which an individual’s blood has a low platelet count. Platelets are important for blood clotting, which is critical in repairing blood vessel damage. So, a low platelet count can cause mild to serious internal and/or external bleeding to occur without cessation.6 It can be a fatal if bleeding is not stopped.

HOXA13 heterozygous mutations cause hand-foot-genital syndrome and Guttmacher syndrome. Hand-foot-genital syndrome is characterized by “limb malformations and urogenital defects”.4 It affects the development of hands, feet, reproductive system, and the urinary tract. People that are affected by this syndrome usually have unusually short thumbs and big toes, short feet, small fifth fingers that may curve, and delayed bone formation in their wrists and ankles. Urogenital defects may occur in the form of constant and reoccurring urinary tract infections. Another side effects of this syndrome is infertility. Some females can experience problems during early development of their uterus, which can lead to an increased risk of pregnancy loss, premature labor, and stillbirth.

Mutations in HOXA13 are also responsible for Guttmacher syndrome. This syndrome is a lot like hand-foot-genital syndrome, but it also encompasses additional limb malformations. Some defects include polydactyly of the hands and uniphalangeal second toes with missing nails. This mutation is really rare and has only been studied in three people.

HOX1B mutations cause congenital facial palsy, hearing loss, strabismus, midface retrusion, and upturned nose. There are four people diagnosed with HOX1B mutations. Some of them also experienced feeding difficulties, speech delay, and posteriorly rotated ears. These malformations caused the people to experience facial weakness, which impaired their ability to control their facial expressions. It was very hard for them to smile or even move their face.

Mutations in HOXB13 are associated with early-onset prostate cancer and may be associated with breast cancer and colorectal cancer. Early onset cancer is the only risk factor that increases with HOXB13 mutations. No other phenotypic defects have been identified thus far. HOXB13 is important in prostate development, studies have shown that a missense mutation of HOXB13 (G84E) is associated with an increased risked for developing prostate cancer. In a study Charles M. Ewing showed that the HOXB13 mutation was found in 3.1% of men with early-onset of prostate cancer. This was somewhat significant compared to the percentage of men with late-onset prostate cancer that had HOXB13 mutations (0.6%). 8 Studies have yet to show a statistically significant correlation between HOXB13 mutations and the development of early onset breast cancer and colorectal cancer.

HOXC13 mutations cause ectodermal dysplasia 9. This is a type of hair and nail dysplasia. HOXC13 is unique because it does not appear to be expressed in spatial collinearity. It is actually expressed in the papillae of the tongue and in body hair.

HOXD4 mutations cause skeletal anomalies, which can include bilateral cervical ribs and right sacralization of L5.

HOXD10 mutations caused no nerve conduction.

HOXD13 mutations cause brachydactyly type D, E, and V.

It is now a well-established concept that Hox genes play an important role in the development of all of the main axes of an embryo, especially the anterior-posterior axis.