The protocadherin 11X/Y (PCDH11X/Y) gene pair as determinant of cerebral asymmetry in modern Homo sapiens

Abstract

Annett's right-shift theory proposes that human cerebral dominance (the functional and anatomical asymmetry or torque along the antero-posterior axis) and handedness are determined by a single "right-shift" gene. Familial transmission of handedness and specific deviations of cerebral dominance in sex chromosome aneuploidies implicate a locus within an X-Y homologous region of the sex chromosomes. The Xq21.3/Yp11.2 human-specific region of homology includes the protocadherin 11X/Y (PCDH11X/Y) gene pair, which encode cell adhesion molecules subject to accelerated evolution following the separation of the human and chimpanzee lineages six million years ago. PCDH11X and PCDH11Y, differentially regulated by retinoic acid, are highly expressed in the ventricular zone, subplate, and cortical plate of the developing cerebral cortex. Both proteins interact with β-catenin, a protein that plays a role in determining axis formation and regulating cortical size. In this way, the PCDH11X/Y gene pair determines cerebral asymmetry by initiating the right shift in Homo sapiens.

Figure 1

The BBC Internet survey. Mental rotation (top) and verbal fluency/reasoning (bottom) test scores, as functions of writing hand preference. Note the better performance by males for the mental rotation task and by females for the verbal fluency/reasoning task. Data adapted from Ref. .

Figure 2

The Xq21.3/Yp11.2 reduplicative translocation. The creation of the human Yp11.2 region began 6 million years ago when the Xq21.3 block was duplicated onto the hominin Y chromosome. The Yp11.2 block inverted at a later date (presently unknown), PABPC5 was deleted, and TGIF2LY was truncated.

Figure 3

PCDH11X/Y isoforms and sequence differences. PCDH11X (top) and PCDH11Y (middle) isoforms differ principally in their cytodomains and signal peptides, shown in color. There are several amino acid differences between PCDH11X and PCDH11Y (bottom). EC1–7, ectodomains 1–7; β, β-catenin binding site; 1–3, conserved motifs 1–3.

Figure 4

Proposed mechanism by which PCDH11X/Y alters cortical surface area along the A–P axis. PCDH11X/Y tetramers, stabilized by disulphide bonds (S), are shown at the surface of neuronal precursors within the ventricular zone (VZ). In the left-frontal region (and right-occipital region, omitted for clarity) PCDH11X/Y inhibits protein phosphatase 1α (PP1α). This stimulates the degradation of β-catenin (β-cat) by enhancing the activity of glycogen synthase kinase 3β (GSK-3β). β-Catenin can no longer coactivate transcription with T cell (TCF) and lymphoid enhancement factors (LEF) and the cell stops dividing symmetrically and begins asymmetric division preventing the pool of neuronal precursors from expanding. In the right-frontal region (and left-occipital region, omitted for clarity) PCDH11X/Y protects β-catenin from degradation by GSK-3β. β-Catenin can coactivate transcription with TCF and LEF, and the cell continues dividing symmetrically, thus increasing the pool of neuronal precursors before the phase of asymmetric division, leading to an increase in the number of cell columns within the cortical plate (CP). See the text for further information.