Sandra L. Gilbert

Accelerated Evolution of Nervous System Genes in the Origin of Homo sapiens

Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, we examined the evolution of genes involved in diverse aspects of nervous system biology. We found that these genes display significantly higher rates of protein evolution in primates than in rodents. Importantly, this trend is most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution is most prominent in the lineage leading from ancestral primates to humans. Thus, the remarkable phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. In addition to uncovering broad evolutionary trends, our study also identified many candidate genes--most of which are implicated in regulating brain size and behavior--that might have played important roles in the evolution of the human brain.

Regulation of the α-secretase ADAM10 by its prodomain and proprotein convertases

Ectodomain shedding of the Alzheimers amyloid precursor protein is mediated by α‐ and β‐secretases, which, for their part, are also proteolytically processed. The disintegrin metalloproteinase ADAM10 is synthesized as a zymogen with a proprotein convertase (PC) recognition sequence between the prodomain and the catalytic domain. In this study, we investigated the role of the prodomain in the regulation of the α‐secretase activity of ADAM 10. Overexpression of the proprotein convertases PC7 and furin in human embryonic kidney 293 cells revealed an increased ADAM10 maturation resulting in enhanced α‐secretase‐mediated processing of amyloid precursor protein. Mutation of the PC recognition sequence in ADAM10 as well as the use of a PC inhibitor and of the furin‐deficient LoVo cell line confirmed the role of PCs, in particular, of PC7, in ADAM10 maturation and activation. Furthermore, we demonstrated that the prodomain of ADAM10 has a dual function. When coexpressed in trans as separate polypeptide, it inhibited the α‐secretase activity of wild‐type ADAM10. However, the prodomain acted as a chaperone and functionally rescued the α‐secretase activity of a former inactive ADAM10 mutant lacking the prodomain. The results of our study suggest new approaches to enhance the nonamyloidogenic α‐secretase pathway.

Genetic links between brain development and brain evolution

The most defining biological attribute of Homo sapiens is its enormous brain size and accompanying cognitive prowess. How this was achieved by means of genetic changes over the course of human evolution has fascinated biologists and the general public alike. Recent studies have shown that genes controlling brain development — notably those implicated in microcephaly (a congenital defect that is characterized by severely reduced brain size) — are favoured targets of natural selection during human evolution. We propose that genes that regulate brain size during development, such as microcephaly genes, are chief contributors in driving the evolutionary enlargement of the human brain. Based on the synthesis of recent studies, we propose a general methodological template for the genetic analysis of human evolution.

Apaf-1 deficiency and neural tube closure defects are found in fog mice

The forebrain overgrowth mutation (fog) was originally described as a spontaneous autosomal recessive mutation mapping to mouse chromosome 10 that produces forebrain defects, facial defects, and spina bifida. Although the fog mutant has been characterized and available to investigators for several years, the underlying mutation causing the pathology has not been known. Because of its phenotypic resemblance to apoptotic protease activating factor-1 (Apaf-1) knockout mice, we have investigated the possibility that the fog mutation is in the Apaf-1 gene. Allelic complementation, Western blot analysis, and caspase activation assays indicate that fog mutant mice lack Apaf-1 activity. Northern blot and reverse transcription-PCR analysis show that Apaf-1 mRNA is aberrantly processed, resulting in greatly reduced expression levels of normal Apaf-1 mRNA. These findings are strongly suggestive of the fog mutation being a hypomorphic Apaf-1 defect and implicate neural progenitor cell death in the pathogenesis of spina bifida—a common human congenital malformation. Because a complete deficiency in Apaf-1 usually results in perinatal lethality and fog/fog mice more readily survive into adulthood, these mutants serve as a valuable model with which apoptotic cell death can be studied in vivo.

Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of γ-aminobutyric acid type A (GABAA) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABAA receptors. Our data implicate Trak1 as a crucial regulator of GABAA receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

Hereditary hyperekplexia caused by novel mutations of GLRA1 in Turkish families

AbstractBackground: Hyperekplexia, also known as startle disease or stiff-person syndrome, is a neurological condition characterized by neonatal hypertonia and a highly exaggerated startle reflex. Genetic studies have linked mutations in the gene encoding glycine receptor α1 (GLRA1) with hereditary hyperekplexia. Methods: We analyzed four Turkish families with a history of hyperekplexia. Genomic DNA was obtained from members of these families, and the entire coding sequence of GLRA1 was amplified by PCR followed by the sequencing of PCR products. DNA sequences were analyzed by direct observation using an electropherogram and compared with a published reference sequence. Results: We identified three novel mutations in GLRA1. These included a large deletion removing the first 7 of 9 exons, a single-base deletion in exon 8 that results in protein truncation immediately after the deletion, and a missense mutation in exon 7 causing a tryptophan-to-cysteine change in the first transmembrane domain (M1). These mutant alleles have some distinct features as compared to previously identified GLRA1 mutations. Our data provides further evidence for mutational heterogeneity in GLRA1. The new mutant alleles reported here should advance our understanding of the etiology of hyperekplexia.

Corrigendum: Trak1 mutation disrupts GABA A receptor homeostasis in hypertonic mice

Nat. Genet. 38, 245–250 (2005). The name of the fourth author has now been included in the author list. Jeffrey R. Anderson is at the Howard Hughes Medical Institute and Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.