The role of PAX6 gene in human brain development

Introduction of gastrulation and neurulation

Gastrulation and neurulation are the processes that develop the brain in most vertebrates. Gastrulation is shown below in figure 1.

Figure 1. The figure aboves show the overall process of gastrulation from

In words, gastrulation takes the single-layered blastula and forms the gastrula (not shown). This gastrula is three-layered structure consisting of the ectoderm, mesoderm and endoderm.

The mesoderm forms the notochord and during the third week of gastrulation and the notochord sends signaling cells to the ectoderm resulting in the ectoderm becoming the neuroectoderm. This neuroectoderm gives rise to the neural plate and is the first major stage of neurulation (Larsen, W. J., L. S. Sherman, et al., 2001).

The neural plate then folds outward to form neural grooves which are comprised of neural folds. These folds close shut to form the neural tube to begin neurulation (Larsen, W. J., L. S. Sherman, et al., 2001).

Formation of the human brain: Neurulation

Video overview of neurulation by Amadou Camara

The formation of the brain starts in the fourth week of gastrulation. After the neural tube has developed, its superior part flexes and the level of the future midbrain called the mesencephalon (Larsen, W. J., L. S. Sherman, et al., 2001).

Above the mesencephalon is the prosencephalon and the rhombencephalon lies below the mesencephalon. In the fifth week, the alar plate of the prosencephalon expands to form the cerebral hemispheres, while the basal plate of the prosencephalon becomes the diencephalon (Larsen, W. J., L. S. Sherman, et al., 2001).

The diencephalon, mesencephalon, and the rhombencephalon constitute the brain stem of the embryo. The rhomencephalon folds in a posterior fashion causing the alar plate to flare and form the fourth ventricle of the brain (Larsen, W. J., L. S. Sherman, et al., 2001).

The rhombencephalon also gives rise to the pons, cerebellum, and medulla oblongata. The pons and cerebellum form from the upper part of the rhombencephalon and the medulla oblongata comes from the lower portion of the rhombencephalon (Larsen, W. J., L. S. Sherman, et al., 2001).

Importance of understanding the role of genes

With these complex steps in brain development, one can imagine the numerous amounts of genes that are involved in brain development. Why do we need to know the importance of such genes? Understanding the roles of specific genes in brain development can lead to earlier detection of certain diseases and advancements in stem cell research.

What role does PAX6 gene play in neurulation?

The PAX6 gene is responsible for instructing cells in embryonic development to differentiate into cells of the brain. Pax6 genes are in almost all cells of the neuroectoderm. It also produces a large amount of cortical cells which play a substantial role in brain development (Devitt, 2010).

By conducting a Northern blotting test, the authors in Callaerts, P., G. Halder, et al. were able to see that Pax-6 was first observed in embryonic development when the somites were formed and the neural folds began to close in the cervical region. Expression was first seen in the prosencephalon and rhombencephalon. Later in development, Pax-6 transcripts were present in the telencephalon, diencephalon, and in the myelencephalon. The roof of the mesencephalon was devoid of Pax-6 transcripts. In the neural tube, Pax-6 expression extended along the entire anteroposterior axis up to the rhombencephalic isthmus, which delineates the midbrain-hindbrain boundary. The head surface ectoderm will give rise to the nasal placodes and to the eye placodes. Pax-6 expression in the head surface ectoderm became restricted to the placodes, as they form, and continued to be expressed in the developing lens, cornea, and olfactory epithelium. Pax-6 was also expressed in the optic vesicle and the olfactory bulb, the neural parts of the eye and nose(Figure 2 B and C) (Callaerts, P., G. Halder, et al., 1997).

Figure 2. This figure shows the Pax-6 expression in mouse from “PAX-6 in development and evolution.” (B) At day E10.5 of embryonic development, Pax-6 expression is observed in the lens pit (lp) and in the developing optic stalk (os). (C ) Transverse section showing Pax-6 expression at day E13.5 of embryonic development in lens (le), neuroretina (nr), optic stalk (os), and future cornea (arrowhead).

The expression patterns of PAX6 in the different compartments of the brain

Figure 3. This figure shows the Pax-6 expression in mouse from “PAX-6 in development and evolution.” (A) Schematic representation of the expression of Pax-6 in mouse embryonic brain at day E13 p.c. Terms: cb, cerebellum; et, epithalamus; fc, frontal cortex; fi, fovea isthmi; lv, lateral ventricle; ob, olfactory bulb; oe, olfactory epithelium; sc, spinal cord; vt, ventral thalamus. This is explained in more detail below.


Pax-6 is first expressed in the neuroepithelium of the prosencephalon. Expression in the telencephalon is restricted to the ventricular zone of the lateral and dorsal neural epithelium. The basal telencephalon is devoid of Pax-6 transcripts. In the developing diencephalon, Pax-6 is strongly expressed in the mantle zone of the ventral thalamus and anterior hypothalamus. Pax-6 transcripts are detected in the ventricular zone of the epithalamus and in the precommissural and commissural zones of the pretectum. The posterior commissure delineates the caudal limit of expression of Pax-6 in the diencephalon. In the adult brain, Pax-6 is expressed in discrete areas of the forebrain: the olfactory bulb, the lateral and medial septal nucleus, the horizontal and vertical limb of the diagonal band nucleus, the nuclei of the basolateral complex of the amygdala, some cells of the ventral pallidum, the entopeduncular nucleus, and the zona incerta and its extension into the thalamic reticular nucleus (Callaerts, P., G. Halder, et al., 1997).


The expression of Pax-6 in the tegmentum of the mesencephalon extends laterally into the presumptive region of the differentiating substantia nigra. Strong expression is also observed in the area of the differentiating dorsal raphe. In the young adult brain, Pax-6 expression is observed in the dorsolateral part of the substantia nigra reticularis, in the rostral part of the midbrain central gray, in some scattered cells in the ventral tegmental area, and in the deep mesencephalic nucleus (Callaerts, P., G. Halder, et al., 1997).


The initial expression of Pax-6 in the rhombencephalon resolves into expression in discrete areas of the metencephalon (pons and cerebellum) and myelencephalon (medulla). Pax-6 is expressed in the ventricular zone and the external germinative layer of the developing cerebellum. The EGL later produces the granular cell layer of the cerebellum, where Pax-6 is still expressed in the mature brain. In the young adult brain, Pax-6 is expressed in different nuclei in the pons, medulla, and in both ventricular and external granular layers of the cerebellum (Callaerts, P., G. Halder, et al., 1997).

Mutations of PAX6 gene and their effect on brain development

Haploinsufficiency of PAX6 causes the absence or hypoplasia of the anterior commissure, decreased volumes of the corpus callosum, smaller brain size, and aniridia. The 11p12-13 locus covering PAX6 gene is suggested as one of the autism linkage loci. PAX6 haploinsufficiency may give rise to subtle abnormality in brain structures, which may lead to developmental disorders like autism (Osumi, N. et al., 2010).

Heyman et al. (1999) provided more cognitive impairments are associated with PAX6 mutations. The authors noted a peculiar behavioral phenotype that is segregated with a PAX6 mutation. The individuals studied showed impulsivity, social ineptness, and disinhibition (Heyman et al.  1999). Subsequent fMRI studies of these individuals resulted in identification of both structural and functional brain abnormalities. Additionally, children with PAX6 anirida and no obvious cognitive delay were found to have significantly smaller corpus callosi and anterior commissures and had difficulty processing auditory information compared to children without  PAX6 mutations. It is also interesting to note that over half of these individuals with PAX6 mutations also showed difficulty with understanding spoken language. This impairment is also often seen in children with Asperger Syndrome or high-functioning autism (Davis, 2008).

The link between PAX6 mutation and autism can not be clarified 100%. More studies will need to continue in order to get closer to an actual answer between the two.

The novel mutation in PAX6, novel mutation (c.475_491del17) generates a frameshift and a premature termination 12 codons downstream (p.Arg38ProfsX12),  is predicted to result in a transcript that is recognized by the nonsense-mediated mRNA decay system, leading to a half reduction of PAX6 protein. This suggests that mutations that introduce a premature termination codon (PTC) into the open reading frame usually result in the aniridia phenotype.

Discussion of PAX6 gene importance in brain development

In practical terms, knowledge on the role of PAX6 gene will help scientists refine and improve techniques for making specific types of neural cells. Such cells will be critical for future research, developing new models for disease, and may one day be used in clinical settings to repair the damaged cells that cause such conditions as Parkinson’s disease and amyotrophic lateral sclerosis or Lou Gehrig’s disease (Devitt, 2011).

In Devitt’s 2011 article, Xiaoqing Zhang, a University of Wisconsin-Madison neuroscientist elaborates on this importance, “This gives us a precise and efficient way to guide stem cells to specific types of neural cells. We can activate this factor and convert stem cells to a particular fate. Until now, for any organ or tissues, we didn’t know any determinant factors. This is the first.”

The novel deletion mutation of PAX6, mentioned in previous section, is shown in a Chinese family with aniridia and congenital cataract. This finding expands the mutation spectrum of PAX6 and is useful and valuable for genetic counseling and prenatal diagnosis in families with aniridia accompanied with congenital cataract (Cai, F., J. Zhu, et al., 2010).

The Role of PAX6 Gene in Human Brain Development: Bibliography

Cai, F., J. Zhu, et al. (2010). “A novel PAX6 mutation in a large Chinese family with aniridia and congenital cataract.” Mol Vis 16: 1141-1145.

Callaerts, P., G. Halder, et al. (1997). “PAX-6 in development and evolution.” Annu ReNeurosci 20: 483-532.

Davis, L., K. Meyer, et al. (2008). “Pax6 3′ deletion results in aniridia, autism and mental retardation.” Human Genetics 123(4): 371-378.

Devitt, Terry (2011). “Gene Regulating Human Brain Development Identified.” University of Wisconsin Madison News.30 March 2011. <>

Heyman, I. et al. (1999). “Psychiatric disorder and cognitive function in afamily with an inherited novel mutation of the developmentalcontrol gene PAX6.” Psychiatr Genet 9:85–90

Larsen, W. J., L. S. Sherman, et al. (2001). Human embryology. New York, Churchill Livingstone: 37-112

Osumi, N. et al. (2010). “Evaluation of Pax6 mutant rat as a model for autism.” Plos One 5.12: e15500. MEDLINE with Full Text. EBSCO. Web. 30 Mar. 2011.

2 Responses to The role of PAX6 gene in human brain development

  1. Caryl Thurmon says:

    I had a grandson who died at two months of age. The Medical Examiner stated that Jacen was born without a Penial gland. I am very interested in finding solid medical research concerning this condition and the effects such a condition has on the brain, development, quality of life, ect. The Medical Examiner stated that because Jacen was a breastfed baby that this may have prolonged his life because Melatonin appears in breast milk. I am finding many articles concerning the Penial gland, Melatonin, PAX 6 (which led me to this article), autism, the Third Eye, having no soul ect. However, as stated previously, I am interested in finding sound medical research concerning a correlation between the Penial gland, or lack of and causes and effects that this condition has on the brain.

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