Rainer W. Guillery and the genetic analysis of brain development

Abstract

Ray Guillery had broad research interests that spanned cellular neuroanatomy, but was perhaps best known for his investigation of the connectivity and function of the thalamus, especially the visual pathways. His work on the genetics of abnormal vision in albino mammals served as an early paradigm for genetic approaches for studying brain connectivity of complex species in general, and remains of major relevance today. This work, especially on the Siamese cat, illustrates the complex relationship between genotype and physiology of cerebral cortical circuits, and anticipated many of the issues underlying the imperfect relationship between genes, circuits, and behavior in mammalian species including human. This review also briefly summarizes studies from our own lab inspired by Ray Guillery's legacy that continues to explore the relationship between genes, structure, and behavior in human cerebral cortex.

Keywords: Siamese cat; brain development; cerebral cortex; genetics.

Figure 1.

The Siamese cat abnormality, as an example of albino abnormalities in mammals. Taken from Kaas (Kaas, 2005) (with permission), the left panel illustrates the normal pattern of partial decussation of visual fibers from the retina to the geniculate, and their normal pattern of projection to visual cortex. The right panel summarizes the abnormal patterns of decussation seen in the Siamese cat, in which fibers from temporal retina that normally project ipsilaterally undergo abnormal crossing at the optic chiasm. This panel also illustrates the two ways in which this abnormal visual input is corrected at the level of the visual cortex, either by a relatively normal pattern of geniculocortical projection (along with relative suppression of the abnormal input) in Midwestern Siamese cats, or reorganization and re-mapping of the abnormal input in the Boston cats.

Figure 2.

Periventricular nodular heterotopia. The first image (A), shows an axial MRI scan from a normal individual, showing the normal configuration of the cerebral cortex, and ventricular lining. The ventricles show white matter signal right down to the ventricular surface, except for a small part of the ventricle shown on the left side where the body of the caudate nucleus appears near the ventricular surface. The middle image (B) shows an MRI scan of a woman with periventricular nodular heterotopia due to a mutation in the FLNA gene, in this case a de novo mutation not shared by her parents. The small arrows highlight the continuous lining of the ventricular surface on both sides with irregular nodules that show identical signal characteristics to normal cerebral cortex. Figure C is adapted from Christodoulou et al (2012) (with permission) and shows resting-state functional connectivity MRI with bold oxygenation level-dependent (BOLD) imaging. The periventricular nodules in this patient are highly active, and their activity is synchronized with overlying cortex, suggesting that these abnormally placed nodules are structurally and functionally integrated into cerebral cortical circuits.

Figure 3.

Diverse human brain malformations. The panel shows axial MRI scans from a normal individual (E) surrounded by MRI scans of brains from 8 individuals with Mendelian disorders of cerebral cortical development. A, perisylvian polymicrogyria, presents with normal patterns of cortical folding frontally and posteriorly, with disrupted gyral folding in the perisylvian region (arrows). These patients have a wide range of intellectual and epilepsy phenotypes from almost normal to severely epileptic and intellectually disabled. B shows bilateral frontoparietal polymicrogyria, reflecting biallelic mutation in GPR56, associated with severe intellectual and motor disability. C shows classical lissencephaly, with a smooth, thick cortex, reflecting abnormal neuronal migration, and associated with intractable neonatal epilepsy, severe motor disability, and usually early death. D shows “double cortex” syndrome, in this case due to a female with heterozygous mutations in the X-linked DCX gene, and again showing a very wide range of phenotypes, generally proportional to the thickness of the abnormal subcortical band of neurons, and including intellectual disability and seizures. F shows Walker-Warbug lissencephaly, also associated with severe disability, intractable epilepsy, and early death. G shows periventricular nodular heterotopia, with the abnormally located neurons highlighted by arrows, and associated with FLNA mutation. This condition is generally associated with normal intelligence and variable seizures, and with some patients being clinically asymptomatic altogether. H shows primary microcephaly, in this case due to biallelic mutation in ASPM, and associated with a cortex that is 50–60% reduced in volume, but relatively normally patterned, with normal cortical thickness, and associated with good motor function, intellectual disability, but usually some language development. I shows a patient with complex microcephaly with simplified and abnormal gyral patterning, in this case reflecting biallelic mutation in WDR62, and associated with more severe intellectual disability and motor delay.

Figure 4.

Hemimegalencephaly before and after hemispherectomy. The entire right hemisphere was removed because of intractable epilepsy, replaced by mere cerebrospinal fluid (bright white). The child, who had suffered dozen of seizures a day, and was weak on the left because of the abnormal hemisphere, did very well after the surgery, going on to learn to walk, speak fluently, and read at grade level. Adapted from Poduri et al (Poduri et al., 2012).