SLIT-ROBO Rho GTPase activating protein 2C is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
in humans that is encoded by the SRGAP2C
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Cortical development gene Slit-Robo Rho GTPase-activating protein 2 (
SRGAP2) has been highly conserved over mammalian evolution, and human is the only lineage wherein gene duplications have occurred (three times). The promoter and first nine exons of SRGAP2 duplicated from 1q23.1 (
SRGAP2A) to 1q21.1 (
SRGAP2B) ~3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (
SRGAP2D) ~2.4 and ~1 mya, respectively. Ancestral SRGAP2A and the derived SRGAP2C copy are fixed at diploid copy number two. In contrast, the SRGAP2B and SRGAP2D are highly copy number polymorphic, with normal individuals identified that completely lack these paralogscopies. SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Incomplete duplication created a novel gene function—antagonizing parental SRGAP2 function immediately “at birth” 2–3 mya, which is a time corresponding to the transition from
Australopithecus
''Australopithecus'' (, ; or (, ) is a genus of early hominins that existed in Africa during the Pliocene and Early Pleistocene. The genera ''Homo'' (which includes modern humans), ''Paranthropus'', and ''Kenyanthropus'' evolved from some ''Aus ...
to
Homo
''Homo'' () is a genus of great ape (family Hominidae) that emerged from the genus ''Australopithecus'' and encompasses only a single extant species, ''Homo sapiens'' (modern humans), along with a number of extinct species (collectively called ...
and the beginning of
neocortex
The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...
expansion.
SRGAP2C is expressed in the human brain and dimerizes with ancestral SRGAP2 to antagonize it. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. SRGAP2C phenocopies SRGAP2 deficiency and underlies sustained radial migration and results in the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. It appears that the SRGAP2C ultimately assumed the antagonistic function of the SRGAP2B duplicate, which shows evidence of pseudogenization in contemporary humans. It is unlikely that SRGAP2B and SRGAP2D are now functional as SRGAP2B has a markedly reduced expression in human brain compared to SRGAP2C and the transcripts produced by SRGAP2D lack two internal exons, leading to a premature termination codon.
SRGAP2B and SRGAP2C are necessary in the protracted synaptic maturation of human neurons.
They act on ancestral molecular pathways that involve SRGAP2 and SYNGAP1, a major gene involved in neurodevelopmental disorders.
References
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