Then, a few years later, it was shown that autosomic recessive mutations of the RELN gene were linked to a form of lissencephaly with cerebellar hypoplasia (LCH), with associated findings suggested that RELN was linked to some neuropsychiatric conditions, and RELN was demonstrated to be reduced in the cerebellum of autistic patients after Western blotting and immunodetection. Shortly after the original discovery, it became clear that the mouse gene ( reln) had a very high homology to that in humans ( RELN). Contrarily to the mutants, the phenotype of heterozygous Reeler mice ( reln +/−) is normal, but, interestingly, these animals may be translational models of certain human neuropsychiatric disorders. Behaviorally, the latter consists of dystonia, ataxia, and tremor structurally it primarily affects the design of the cerebral cortex, hippocampus, and cerebellum. Consequently, only homozygous recessive Reeler mice ( reln −/−) are totally devoid of Reln and have a definite phenotype. The mutation is autosomic and shows recessive transmission. The name was given to the protein after the detection of its coding gene, and the acknowledgement that its lack was causative of the mouse Reeler mutation, which was described, about half a century before, consisting in a form of ataxia. Neuronal migration and precise setting during neurogenesis depend, among others, on reelin (Reln), a 388 kDa glycoprotein secreted by certain neurons within the extracellular matrix. Description of face validity, i.e., the resemblance of phenotypes between the two species, centers onto the histological, neurochemical, and functional observations in the cerebral cortex, hippocampus, and cerebellum of Reeler mice and their human counterparts. The worth of these mice as translational models is discussed, with focus on their construct and face validity.
According to their modalities of inheritances and with significant differences among each other, these neuropsychiatric disorders can be modeled in the homozygous ( reln −/−) or heterozygous ( reln +/−) Reeler mouse. Besides LIS2 and ADLTE, RELN and/or other genes coding for the proteins of the Reln intracellular cascade have been associated substantially to other conditions such as spinocerebellar ataxia type 7 and 37, VLDLR-associated cerebellar hypoplasia, PAFAH1B1-associated lissencephaly, autism, and schizophrenia. In both human and mice, the gene encodes for a glycoprotein referred to as reelin (Reln) that plays a primary function in neuronal migration during development and synaptic stabilization in adulthood.
The first description of the Reeler mutation in mouse dates to more than fifty years ago, and later, its causative gene ( reln) was discovered in mouse, and its human orthologue ( RELN) was demonstrated to be causative of lissencephaly 2 (LIS2) and about 20% of the cases of autosomal-dominant lateral temporal epilepsy (ADLTE).