Molecular Psychiatry (2001) 6, 129–133  2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00 www.nature.com/mp NEWS & VIEWS mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly

A number of recent reports implicate the Reelin glyco- reeler-like phenotypes (Table 1). These include mouse protein in the etiology of several neurodevelopmental disabled1(Dab1)genemutation,20 double knockout of disorders ie, schizophrenia,1–3 bipolar disorder,2,3 major VLDL and ApoE2 proteins in mouse,21 presenilin 1 depression,2 lissencephaly4 and autism.5,65,66 Moreover, deficient mice,22 Scrambler mouse mutation,23 Yotari converging data point to Reelin as an important modu- autosomal recessive mouse,24 rat mutation creeping,25 lator of a neuronal signaling system that may be involved Emx2 mutant mouse,26 and T-box transcription factor in synaptic transmission and plasticity.6 Iwilldiscuss knockout mice.27 Several experimental paradigms and the various lines of evidence clarifying the role of Reelin various animal models also cause decreases in Reelin in brain development and cell signaling and in the gen- production with cortical and behavioral abnormalities esis of several brain disorders. (Table 2); these include heterozygous reeler mouse Reeler is an autosomal recessive mutant mouse that mutant,28 after x-irradiation,29 prenatal human influenza was first discovered nearly 50 years ago.7 This viral infection,30–33 domoic acid lesion of Cajal–Rezius mutation produced an ataxic and reeling gait in the cells,34 after thromboxane A2 treatment35 and in experi- affected mice. Analysis of the mental hypothyroidism.36 Of interest, are several brain in the mutant mouse revealed multiple defects such as structural and functional deficits which have been inverted cortical lamination, abnormal positioning of observed in heterozygous reeler mutation28 and in pro- neurons and aberrant orientation of cell bodies and geny of mouse mothers exposed to human influenza viral fibers.7,8 In the of the reeler mouse, neu- infections,30–33 that are similar to those found in adult rons destined to form the subplate zone occupy ectopic patients with schizophrenia, such as 50% reduction in positions in superficial cortical layers. Additionally, Reelin protein,1–3 abnormal prepulse inhibition28 (Shi, neurons developed later which are destined to form the Fatemi, Patterson, unpublished data) and alterations in cortical plate, fail to bypass previously generated neu- density of nNOS containing cells in the neocortex.28,33 rons.8 Thus, an inverted pattern of cortical develop- Reelin is a glycoprotein with a relative molecular ment takes place in the mutant mice. Moreover, pro- mass of 388 kDa, which was discovered in 1995.13,14 found cerebellar hypoplasia is evident in brains of The reelin cDNAs have been cloned in mouse14,37 and reeler-mutant mice.9–11 Reelin RNA is first detectable in man.38 Based on cDNA sequence, Reelin is a in the mouse embryonic brain on day 9.5.12 It then secretory extracellular matrix protein,39 composed of increases in concentration up to early postnatal days 3461 animo acids.40 Reelin’s structure contains a signal and then declines to adult levels. The first cells pro- peptide followed by a N-terminal sequence similar to ducing Reelin are the Cajal–Retzius neurons which F-spondin and a hinge region upstream from eight begin differentiation as early as day 9.5 in the embry- Reelin repeats of 350–390 amino acids.40 Each Reelin onic mouse brain;13 these are transient neurons that act repeat is composed of two subrepeats separated by an as pathfinders and help in the early laminar organiza- EGF motif.40 The Reelin protein ends with a highly tion of the cortex.13,14 In the adult mammalian brain, basic C-terminus composed of 33 amino acids essential Reelin is localized to layer I cortical Cajal–Rezius cells, for secretion. Multiple antibodies specific against C-ter- cortical GABAergic in layers II through minal40 and N-terminal epitopes of Reelin13,40 have VI,1,15 cerebellar granular cells16 and hippocampal been produced and used successfully in western blot- interneurons.2 Reelin is also present in a number of ting and immunocytochemical studies of Reelin struc- embryonic sites such as embryonic spinal cord,17 sub- ture and function.1–4,66 The CR-50 epitope recognized pial granular layer of fetal human cortex18 and by CR-50 antibody13 is located near the N- terminus39 developing rat .19 and is composed of amino acids 230–346 of Reelin pro- Recent explosion of knowledge about the localization tein.41 The CR-50 epitope is essential for Reelin–Reelin and function of Reelin has resulted in discovery of a electrostatic interaction, which produces a soluble number of other mutations, which result in similar string-like homopolymar, composed of up to 40 or more regularly-repeated monomers, which form both in vitro, and in vivo.41 Mutated Reelin, lacking a CR- 50 epitope fails to form such a homopolymer and is Correspondence: SH Fatemi, MD, PhD, Department of Psychiatry, 41 Division of Neuroscience Research, University of Minnesota thereby unable to transduce the Reelin signal. 42–46 Medical School, Box 392 Mayo Building, 420 Delaware Street SE, Recent work by several laboratories point to mul- Minneapolis, MN 55455, USA. E-mail: [email protected] tiple proteins as likely receptors for Reelin binding. News & Views 130 Table 1 Reeler-like phenotypes in various mutations and knockout gene constructs

Type of mutation Protein affected Findings Reference

Yotari ↓ Disabled-1 normal Reelin expression 48 cortical lamination defect Scrambler ↓ Disabled-1 normal Reelin expression 20,47 cortical lamination defect VLDL and ApoE2 ↑ Disabled-1 normal Reelin expression 21 double knockout cortical lamination defect Presenilin 1 deficiency ↓ Presenilin-1 cortical dysplasia 22 ↓ CR cells Rat creeping mutation homologous to ↓ Reelin 25 mouse reeler cortical lamination defect EmX2 mutation Emx2 null allele absent Reelin in marginal zone 26 T box transcription ↓ Tbr-1 laminar inversion 27 factor knockout ↓ Reelin Reeler homozygous Autosomal recessive abnormal cortical lamination, 7 mutation no Reelin Reeler heterozygous ↓ 50% Reelin Reelin haploinsufficiency 28 mutation abnormal PPI Reeler Orleans mutation Reelin not cleaved lack of Reelin secretion 40,67 by a metalloproteinase CdK5 ↓ cyclin dependent inverted lamination 63 serine-threonine perinatal death protein kinase p35 ↓ p35, neuronal cortical lamination defects, 64 activation of CdK5 seizures, adult lethality

Table 2 Reelin deficiency or alteration due to various experimental insults

Lesion Findings Reference

Late gestation x-irradiation ↓ Reelin, heterotopic Purkinje cells 29 Domoic acid application ↓ cell migration, ↓ radial , 34 ↑ GFAP Thromboxane A2 treatment ↓ NCAM, ↓ Reelin 35 Perinatal hypothyroidism in newborn rats ↓ Reelin, ↑ Dab-1 in post-natal day 0 rats 36 Effect of prenatal human influenza viral ↓ Reelin, ↑ GFAP, ↑ nNOS, 2,30–32 infection on newborn mice ↑ SNAP-25 in post-natal day 0 mice thinning of cortex and ↑ BDNF administration ↓ Reelin in CR cells 61

These receptors include apolipoprotein E2 (ApoE2), Furthermore, mice that lack either Reelin or both very-low-density lipoprotein (VLDL), Cadherin-related VLDL and ApoE2 receptors exhibit hyperphosphoryl- neuronal receptor (CNR) family and ␣3␤1 integrin pro- ation of the microtubule-stabilizing protein tau,44 caus- tein. Mutations involving VLDL and ApoE221 and ␣3␤1 ing dysregulation of neuronal microtubule function. integrin45 in mice result in defective cortical lami- Another important result of Reelin binding to its recep- nation and abnormal neuronal migration. Additionally, tors involves activation of the focal adhesion tyrosine mutations involving a cytosolic adapter protein, Dis- kinase (FAK) system51 which is a component of a post- abled 1 (Dab 1)47–49 produce cortical abnormalities synaptic mechanism responsible for an increase in the similar to those seen in reeler homozygous mutation.7,9 number of synapses and alterations in postsynaptic Reelin signaling causes tyrosine phosphorylation of spine structure in axons, dendrites, and the intermedi- Dab-1 adapter protein.50 Tyrosine phosphorylation of ate filament cytoskeleton of astrocytes. In addition, Dab-1 protein occurs following Reelin binding to its Reelin may activate serine-threonine kinases putative receptors VLDL, ApoE2 and CNR proteins,44 (P35/Cdk5) and the Srctyrosine kinase family (Fyn-K) facilitating the signaling pathway between Reelin- leading to phosphorylation of adapter protein Dab-1. secreting cells and cortical pyramidal cells. Absence of Phosphorylated Dab-1 may serve as a docking site for ␣3␤1 integrin protein can also cause reduction in Dab- the SH2-domain of the Src-kinase family of proteins 1 levels, adversely affecting Reelin function45 and whose nuclear translocation may underlie synaptic inhibiting neuronal migration. and dendritic spine plasticity.52

Molecular Psychiatry News & Views 131 Recent reports46,53 also implicate the reelin receptor ability to sit or stand unsupported, hypotonia, myopia, ApoE2 protein in recruitment of the C-JunN-Terminal nystagmus and generalized seizures.4 Furthermore, all kinase (JNK-interacting proteins) 1 & 2 (molecular children showed substantial homozygosity involving adapter proteins for JNK-signaling pathway) subserving the RELN locus in chromosome 7q22 with a maximal multiple functions such as regulation of the mitogen- lod score of 4.82; statistical analysis provided signifi- activated protein kinases, cell adhesion, vesicle traf- cant linkage of lissencephaly to chromosome 7q22 ficking, neurotransmission, cellular responses to (PϽ0.00003).4 environmental stress, morphogenesis and regulation of In one family, abnormal splicing of exon 36 of Reelin region-specific apoptosis of neurons during early brain DNA produced a translational frameshift with the development.54,55 This last function may have signifi- addition of 22 missense amino acids, followed by a cant implications in the etiology of a number of neuro- premature termination codon.4 Western blotting of developmental disorders recently connected with serum in these children showed undetectable levels of Reelin dysregulation (see below). Reelin.4 In the second family, abnormal splicing of Several reports now implicate Reelin in the etiology exon 42 produced a translational frameshift with the of neurodevelopmental and psychiatric disorders addition of six missense amino acids followed by an (Table 3).1–5 The first published report1 used northern early termination codon. Western blotting of serum and western blotting and immunocytochemistry to Reelin levels in these children showed reduced Reelin show significant 50% reduction in Reelin mRNA and levels.4 In both affected family members, detection of protein in cerebellar, hippocampal and frontal corteces Reelin repeats beyond 4 and 5 as well as loss of C- of patients with schizophrenia and psychotic bipolar terminal amino acids (required for normal secretion disorder. These authors suggested that Reelin might be and function of Reelin) caused the observed pheno- a vulnerability factor in psychosis.1 They have further typic abnormalities previously described.4 These strik- extended and confirmed these observations in ing mutations indicate that deletions of various lengths additional postmortem frontal cortex of subjects with of Reelin protein may cause either total absence of schizophrenia and psychotic bipolar disorder.3 serum Reelin, as seen in one pedigree vs reduction in Reduction in Reelin was associated with significant levels of serum Reelin seen in the second pedigree.4 decreases in GAD-67 expression in the same postmor- This disparity in levels of Reelin protein production tem brains.3 A later immunocytochemical report2 appears similar to the scenario seen in Reelin homo- showed significant reductions in Reelin immunoreac- zygous mutant mice13 (with no Reelin production) vs tivity in schizophrenic and bipolar patients. However, reeler heterozygous mutation28 and that seen following these authors detected similar decreases in hippocam- prenatal viral infection32 where brain Reelin levels are pal Reelin protein levels in non-psychotic bipolar and reduced by 50%. Moreover, a similar mechanism may depressed subjects2 suggesting that Reelin deficiency be operational in various neuropsychiatric disorders may not be limited to subjects with psychosis alone. where Reelin production may be affected selectively by This finding has now been bolstered by recent findings various mutations causing either profound showing Reelin reductions in autistic subjects5,66 and (schizophrenia, autism, lissencephaly) or milder low or undetectable levels of serum Reelin protein in (bipolar, depressed) cognitive deficits1–5,66 associated several subjects with an autosomal recessive form of with their respective Reelin levels. The overall picture lissencephaly.4 In this report Hong et al4 showed that emerging from these reports suggests that Reelin affected children exhibited congenital lymphoedema deficiency may be associated not only with vulner- and hypotonia. Brain MRI showed moderate lissence- ability to developing psychosis but also to develop- phaly and profound cerebellar hypoplasia. All children ment of cognitive dysfunction, a clinical symptom also showed severe delays in neurological and cogni- often observed in various neuropsychiatric disorders tive development such as little or no language and no such as bipolar disorder,2 major depression,2 autism5,66 and lissencephaly.4 This hypothesis is further sup- ported by animal studies52 linking Reelin-integrin Table 3 Reduction in Reelin in various neuropsychiatric interactions with synaptic plasticity. Association of disorders ApoE2 and LDL receptor family with reelin protein may also link certain neurodegenerative disorders such Disorder Findings Reference as Alzheimer’s dementia6,56 with dysregulation of the Reelin signaling system. ↓ 1,3 Schizophrenia 50% mRNA and In a recent publication (see the current issue), Per- Psychotic bipolar protein sico et al65 presents a significant association between (temporal, frontal, autism and RELN gene variants using case-control and cerebellar) Schizophrenia ↓ protein 2 family-based designs. These investigators assessed this Bipolar disorder (hippocampus) linkage from a pool of 95 Italian autistic patients and Major depression 186 ethnically matched controls. Case-control and fam- Lissencephaly ↓ blood Reelin level 4 ily-based genetic analyses yielded a significant associ- Autism ↓ brain and blood 5,66 ation between autistic disorder and polymorphic GGC Reelin levels repeat located immediately 5Ј of the Reelin gene ATG initiator codon and with specific haplotypes produced

Molecular Psychiatry News & Views 132 by this polymorphism involving two single-base sub- References stitutions located in a splice junction of exon 6 and within the coding sequence of exon 50.65 Extended 1 Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, TDT analysis of the 172 complete trios exhibited pref- Pisu MG et al. A decrease of Reelin expression as a putative vulner- ability factor in schizophrenia. Proc Natl Acad Sci USA 1998; 95: erential transmission of ‘long’ triplet repeat alleles (ie > 15718–15723. 11 repeats) to autistic patients (P < 0.05). Additionally, 2 Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immuno- transmission disequilibrium patterns varied signifi- reactivity in hippocampus of subjects with schizophrenia, bipolar cantly (P < 0.001) between affected and unaffected disorder and major depression. Mol Psychiatry 2000; 5: 654–663. 65 3 Guidotti AR, Auta J, Davis J, Dwivedi Y, Grayson D, Impagnatiello sibs. 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