Neurodevelopmental MACPFs: The vertebrate astrotactins and BRINPs.

Astrotactins (ASTNs) and Bone morphogenetic protein/retinoic acid inducible neural-specific proteins (BRINPs) are two groups of Membrane Attack Complex/Perforin (MACPF) superfamily proteins that show overlapping expression in the developing and mature vertebrate nervous system. ASTN(1-2) and BRINP(1-3) genes are found at conserved loci in humans that have been implicated in neurodevelopmental disorders (NDDs). Here we review the tissue distribution and cellular localization of these proteins, and discuss recent studies that provide insight into their structure and interactions. We highlight the genetic relationships and co-expression of Brinps and Astns; and review recent knock-out mouse phenotypes that indicate a possible overlap in protein function between ASTNs and BRINPs.

Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders.

Background:Brinps 1-3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1-/- mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Method: We created Brinp2-/- mice and Brinp3-/- mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2-/-Brinp3-/- double knock-out mice were generated by interbreeding Brinp2-/- and Brinp3-/- mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1-/-Brinp2-/-Brinp3-/- triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1-/- mice, and examined by weight and histological analysis. Results:Brinp2-/- and Brinp3-/- mice differ in their behavior: Brinp2-/- mice are hyperactive, whereas Brinp3-/- mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3-/- mice also show evidence of altered sociability. Both Brinp2-/- and Brinp3-/- mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2-/- and Brinp3-/- mice, without evidence of new or exacerbated phenotypes. Conclusion:Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2-/- and Brinp3-/- genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.

Brinp1(-/-) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density.

BACKGROUND: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. METHODS: Brinp1 knock-out (Brinp1(-/-)) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. RESULTS: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1(-/-) mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1(-/-) mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1(-/-) mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1(-/-) mice, suggesting that they may ameliorate the effects of Brinp1 loss. CONCLUSIONS: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1(-/-) mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).

Maspin is not required for embryonic development or tumour suppression.

Maspin (SERPINB5) is accepted as an important tumour suppressor lost in many cancers. Consistent with a critical role in development or differentiation maspin knockout mice die during early embryogenesis, yet clinical data conflict on the prognostic utility of maspin expression. Here to reconcile these findings we made conditional knockout mice. Surprisingly, maspin knockout embryos develop into overtly normal animals. Contrary to original reports, maspin re-expression does not inhibit tumour growth or metastasis in vivo, or influence cell migration, invasion or survival in vitro. Bioinformatic analyses reveal that maspin is not commonly under-expressed in cancer, and that perturbation of genes near maspin may in fact explain poor survival in certain patient cohorts with low maspin expression.