The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

Abstract

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). 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. 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. 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. The worth of these mice as translational models is discussed, with focus on their construct and face validity. 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. mutations of the RELN gene were linked to a form of lissencephaly with cerebellar hypoplasia (LCH) [9], with associated findings suggested that RELN was linked to some neuropsychiatric conditions [10], and RELN was demonstrated to be reduced in the cerebellum of autistic patients after Western blotting and immunodetection [11].Determining a good translational mouse model for a neuropsychiatric condition needs construct, predictive, and face validity [12]. Rigorously, construct validity only relates to transgenic mice, but, in a broader definition, it also comprehends the syndromic models and the spontaneous DNA mutations linked to the phenotype under study. In other words, this factor defines the similarity of the disease between the mouse and the human disorder in terms of the causal gene(s) as e.g., deducted from gene association and linkage analysis. As mentioned above, LCH is a human monogenic condition caused by a mutation in RELN. Therefore, the Reeler mouse fully meets the criterion of construct validity for the condition. There is also evidence for genetics to be associated with the etiology of several neuropsychiatric conditions, such as autism and schizophrenia, but, as the result of their multidimensional clinical symptoms, causal gene(s), if any, persist to be undiscovered [13]. Nonetheless, there are numerous genes associated with the human autistic pathology after analysis of Mendelian disorders (syndromes), rare mutations, or association studies; see e.g., [14].Predictive validity, i.e., the similarity of the response to cures in humans and mice is difficult to establish, in the nonexistence of a re...

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

“…8A,C). Consistent with the expression of Reelin by GABAergic neurons (Lossi et al, 2019), Reelin+ cells also co-expressed the vesicular GABA transporter (Scl32a1), a marker of GABAergic neurons (Fig. 8B).…”

“…In humans, Reelin deficiency has been linked to the development of psychiatric disorders (Ishii et al, 2016). Thus, the HR mice, that expressed lower level of Reelin, have been proposed as a valid animal model to study neurodevelopmental psychiatric disorders (Lossi et al, 2019).…”

Preclinical Models: Boosting Synergies for Improved Translation

“…Out of eleven papers, six are based on animal models [1][2][3][4][5][6], highlighting that these models still play a crucial role in translational medicine, even in a historical moment in which the need to find alternative methodologies is increasingly pressing.…”

“…In this context, the issue raised by some authors about the translational validity of a certain animal model, in this specific case the Reeler mouse, is very timely. Central to the debate is the rare occurrence of the very conditions for which mice homozygous for the Reeler mutation have been created, and the objective difficulty of fully validating the mice expressing the heterozygous genotype as a translational model for more frequent diseases such as autism and schizophrenia [2].…”

“…More specifically, the paper analyses the potential of iPSC-endothelial cells in accelerating tissue regeneration and their suitability to enter progressively more clinical trials. The most represented research field in this Special Issue is tissue morphology [1][2][3]5] followed by tissue engineering [9][10][11] and neuroscience [1][2][3], with one article intercepting both these areas of expertise [12]. This latter work reports, indeed, a method to generate a three-dimensional neuronal system composed of cortical neurons and glial cells derived from iPSCs, suitable for drug screening and disease modeling.…”