The term Cajal–Retzius cells (CR cells) has nowadays been used to identify a heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developmental cerebral cortex and in the immature hippocampus of different species and at different times during embryogenesis and postnatal life.
These cells were discovered by two scientists, Cajal and Retzius, at two different times and in different species. They are originated in the developing brain in multiple sites within the neocortex and hippocampus. From there, CR cells experience migration through the marginal zone, originating the layer I of the cortex.
As these cells are involved in the correct organization of the developing brain, there are several studies implicating CR cells in neurodevelopmental disorders, especially Alzheimer’s, schizophrenia, bipolar disorder, autism, lissencephaly and temporal lobe epilepsy.
Cajal–Retzius cells as drawn by Santiago Ramón y Cajal in 1891
|NeuroLex ID||Cajal-Retzius Cell|
In 1891 Santiago Ramón y Cajal described slender horizontal bipolar cells he had found in an histological preparation of the developing marginal zone of lagomorphs. These cells were then considered by Gustaf Retzius as homologous to the ones he had found in the marginal zone of human fetuses around mid-gestation in 1893 and 1894. He described those cells as having large, horizontal, sometimes vertically orientated somata located at some distance from the pia.
Later on in 1899, Cajal drew the neurons in layer I of the human fetus at term and newborn. The cells laid closer to the pia and displayed smaller, often triangular or pyriform somata, and less complex processes that lacked the ascending branchlets and had a more superficial location than the cells Retzius previously described, The cells' different morphologies and the fact that Cajal and Retzius used different species at different developmental periods led to discussion about the definition of Cajal–Retzius cells. In fact immunohistochemical studies performed at advanced developmental stages in human and macaque cortex visualize cells more similar to the cells Cajal described. In contrast, studies of the human mid-gestation period describe cells closer to the Retzius type.
The early descriptions by Cajal and Retzius referred to the neocortex but similar cells were found since 1994 in the marginal zone of the hippocampus. Various studies then proved the Cajal–Retzius cells as being responsible for the production of reelin,
In 1999 Meyer loosely defined the Cajal–Retzius cells as the family of Reln-immunoreactive neurons in the marginal zone, as so to settle a difference between the pioneer neurons, Reln-negative preplate derivatives that settle in the same area and project to the subcortical area that he had already described in 1998. He also described simpler cells with simpler morphologies in the marginal zone of rodents.
In 2005 Bielle suggested that there were distinct subpopulations of Cajal–Retzius cells in different territories of the developing cortex due to the heterogeneity of transcription factors and the discovery of new sites of origin.
However, a clear classification scheme as so far not been established.
Though still unresolved, studies show that Cajal–Retzius cells have different origins, both in the neocortex and in the hippocampus. At the neocortex they are originated in the local pallium ventricular zone, the pallial-subpallial border of the ventral pallium, a region at the septum  the cortical hem  and retrobulbar ventricular zone.
It has been discovered that in mice, CR cells are generated very early in the development, appearing between 10,5 and 12,5 embryonic days.
Cajal–Retzius cells experience tangential migration in the marginal zone, a superficial layer of the preplate in the cortical neuroepithelium that will originate the layer 1 of the cortex, and according to some studies, this migration is also dependent of the site the cell was first generated, showing a link between this site, the migration and the location of these cells. In 2006 it was demonstrated that the migration in the subpopulation of the cortical hem is controlled by the meninges, using tissue cultures and in vivo manipulations in mice.
Subpopulations of these neurons from the septum and pallial-subpallial border express the homeodomain transcription factor Dbx1 and migrate to the medial, dorsolateral and piriform cortex  and though genetically different from the other subpopulations (Dbx1 negative), all have the same morphological and electrophysiological properties, showing us that even with different origins of CR cells, they get the same characteristics.
In the hippocampus, Cajal–Retzius cells have some of the major characteristics as those in the neocortex and also have different origins, like the ventral cortical hem and dentate-fimbrial neuroepithelium.
It is very difficult to find a CR cell in the adult cortex, because the constant number of these cells and the fact that as the brain grows, the distance between these cells increases, requiring the observation of a great number of preparations to find one of these cells.
Properties and Functions
Immunohistochemical studies (detecting antigens by exploiting the principle of antibodies binding specifically to antigens in biological tissues.) show that CR cells demonstrate the expression of GABA-A and GABA-B receptors, ionotropic and metabotropic glutamate receptors, vesicular glutamate transporters, and a number of different calcium-binding proteins, such as calbindin, calretinin and parvalbumin. CR cells express several genes important in corticogenesis, such as reelin (RELN), LIS1, EMX2, and DS-CAM. In addition, CR cells selectively express p73, a member of the p53 family involved in cell death and survival.
CR cells receive an early serotonergic input, which in mice forms synaptic contacts.
In marginal zone the whole-cell patch-clamp studies (the laboratory technique in electrophysiology that allows the study of single or multiple ion channels in cells) show that CR cells have electrophysiological fingerprints. When CRN injected by a suprathreshold depolarizing current pulse, it expresses a repetitive firing mode. However, when Cajal-Ratzius cells injected by a hyperpolarizing current pulse, it expresses a hyperpolarization-activated inward current (H-current).
Using chloride-containing patch-clamp electrodes, spontaneous postsynaptic currents (sPSCs) were recorded in about 30% of the CR cells in P0-P2 rat cerebral cortex. These sPSCs decreased to about 10% at P4, indicating that CR cells became functionally disconnected during further development. Kirmse and Kirischuk  found that these sPSCs were reversibly blocked by bicuculline, which is a light-sensitive competitive antagonist of GABA-A receptors, suggesting activation of GABA-A receptors in these sPSCs. Moreover, the frequency and amplitude of these sPSCs are not influenced by tetrodotoxin, which inhibits the firing of action potentials in nerves, indicating that these sPSCs are independent on presynaptic action potentials.
In other regions of the immature brain and in immature neocortical pyramidal neurons there are prominent membrane depolarizations in CR cells caused by GABA-A and glycine receptor activation.
A role in brain development
CR cells secrete the extracellular matrix protein reelin, which is critically involved in the control of radial neuronal migration through a signaling pathway, including the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor type 2 (ApoER2), and the cytoplasmic adapter protein disabled 1 (Dab1). In early cortical development in mice, mutations of Dab1, VLDLR, and ApoER2, generate similar abnormal phenotypes, called reeler-like phenotype. It perform several abnormal processes in brain development, such as forming an outside to inside gradient, forming cells in an oblique orientation. Therefore, CR cells control two processes: detachment from radial glia and somal translocation in the formation of cortical layers. In addition, the reeler type also manifest a poor organization of the Purkinje cell plate(PP) and the inferior olivary complex(IOC).
Cajal–Retzius cells are, as said before, involved in the organization of the developing brain. Problems in migration, especially those that arise from the lack of reelin production, may influence brain development and lead to disorders in brain’s normal functioning.
The reeler mutant mouse was described in the 1950s by Falconer as a naturally occurring mutant. This type of mouse exhibits some behavioral abnormalities, such as ataxia, tremor and hypotonia, which were discovered to be related to problems in neuronal migration and consequently, cytoarchitecture in the cerebellum, hippocampus and cerebral cortex,
It was found later that the mutation causing these disorders was located in the RELN gene which codes for reelin, a glycoprotein secreted by Cajal–Retzius cells in the developing brain. This protein seems to act as a stop signal for migrating neurons, controlling the positioning and orientation of neurons in their layers, according to the inside-out pattern of development. When the mutation occurs, reelin expression is reduced and this signal isn’t as strong, therefore, migration of the first neurons in the brain is not done correctly. The reeler mutant has been used, because of its characteristics, as a model for the study of neuropsychiatric disorders.
Even though Cajal–Retzius cells highly reduce its number after maturation and in adult life, in brains from Alzheimer's disease patients their number is diminished in comparison to normal brains and their morphology is also altered, namely there is a significant reduction of their dendritic arborization, which reduces the number of synapses between these cells and other neurons. On the other hand, as Cajal–Retzius cells are important to the laminar patterning of the brain, their loss may be related to the progressive disruption of the microcolumnar ensembles of the association cortex, which may explain some symptoms of this disease.
Schizophrenia is thought to be of neurodevelopmental origin, that is, there are events in our developing brain between the first and second trimester of gestation that may condition the activation of the pathological neural circuits that lead to its symptoms later in life. It has been hypothesised that abnormal brain lamination is one of the possible causes of schizophrenia. Furthermore, it has been show that in the brains of patients with schizophrenia, as well as in those of patients with bipolar disorder, the glycoprotein reelin is 50% downregulated, which is associated with abnormal DNA methylation of the RELN gene promoter. In the brains of patients with autism, there are also structural abnormalities in the neocortex and levels of reelin are diminished, suggesting the involvement of CR cells in this disorder.
Lissencephaly results from defective neuronal migration between the first and second trimester of gestation which causes lack of gyral and sulcal development, as well as improper lamination, giving the brain a smooth appearance. There are five genes related to lissencephaly, including LIS1, the first to be discovered, and RELN. Apparently Cajal–Retzius cells aren’t affected in case of mutation in LIS1 gene, even though the product of this gene interferes with reelin interaction with their receptors. Mutations in the RELN gene appear in the autosomal form of lissencephaly with cerebral hypoplasia, where patients show developmental delay, hypotonia, ataxia and seizures, symptoms which can be related to the reeler mutant.
In contrast to the previous referred diseases, temporal lobe epilepsy is characterized by a high number prevalence of Cajal–Retzius cells in the adult life, which supposedly causes continuous neurogenesis and migration, thus causing the seizures that characterize this disorder.
- Ramón y Cajal, Santiago (1891). "Sur la structure de l'ecorce cérébrale de quelques mammifères" [On the structure of the cerebral cortex in some mammals]. La Cellule (in Spanish) 7: 123–76.
- Retzius G (1893). "Die Cajal'schen Zellen der Grosshirnrinde beim Menschen und bei Säugetieren" [The Cajal'schen cells of the cerebral cortex in humans and mammals]. Biologische Untersuchungen (in German) 5: 1–8.
- Retzius G (1894). "Weitere Beiträge zur Kenntniss der Cajal'schen Zellen der Grosshirnrinde des Menschen" [Further contributions to the knowledge of the Cajal'schen cells of the cerebral cortex of man]. Biologische Untersuchungen (in German) 6: 29–36.
- Ramón y Cajal S (1899). "Estudios sobre la corteza cerebral humana. I. Corteza visual" [Studies on the human cerebral cortex. I. Visual Cortex]. Revista Trimestral Micrográfica (in Spanish) 4: 1–63.
- Tissir F, Goffinet AM (June 2003). "Reelin and brain development". Nature Reviews. Neuroscience 4 (6): 496–505. doi:10.1038/nrn1113. PMID 12778121.
- Ramón y Cajal S (1899). "Estudios sobre la corteza cerebral humana. II. Estructura de la corteza motriz del hombre y mamíferos superiores" [Studies on the human cerebral cortex. II. Structure of the motor cortex of man and higher mammals]. Revista Trimestral Micrográfica 4: 117–200.
- Ramón y Cajal S (1911). Histologie du système nerveux de l'homme et des vertébrés [Histology of the nervous system of man and vertebrates] 2. Paris: Maloine.[page needed]
- Duckett S, Pearse AG (January 1968). "The cells of Cajal-Retzius in the developing human brain". Journal of Anatomy 102 (Pt 2): 183–7. PMC 1231310. PMID 4296164.
- König N (October 1978). "Retzius-Cajal or Cajal-Retzius cells?". Neuroscience Letters 9 (4): 361–3. doi:10.1016/0304-3940(78)90209-4. PMID 19605246.
- Huntley GW, Jones EG (April 1990). "Cajal-Retzius neurons in developing monkey neocortex show immunoreactivity for calcium binding proteins". Journal of Neurocytology 19 (2): 200–12. doi:10.1007/BF01217298. PMID 2358829.
- Marin-Padilla M (February 1978). "Dual origin of the mammalian neocortex and evolution of the cortical plate". Anatomy and Embryology 152 (2): 109–26. doi:10.1007/BF00315920. PMID 637312.
- Marín-Padilla M (September 1990). "Three-dimensional structural organization of layer I of the human cerebral cortex: a Golgi study". The Journal of Comparative Neurology 299 (1): 89–105. doi:10.1002/cne.902990107. PMID 2212113.
- Supèr H, Soriano E, Uylings HB (June 1998). "The functions of the preplate in development and evolution of the neocortex and hippocampus". Brain Research. Brain Research Reviews 27 (1): 40–64. doi:10.1016/S0165-0173(98)00005-8. PMID 9639671.
- Uylings HB, Delalle I (March 1997). "Morphology of neuropeptide Y-immunoreactive neurons and fibers in human prefrontal cortex during prenatal and postnatal development". The Journal of Comparative Neurology 379 (4): 523–40. doi:10.1002/(SICI)1096-9861(19970324)379:4<523::AID-CNE5>3.0.CO;2-4. PMID 9067841.
- Soriano E, Del Río JA, Martínez A, Supèr H (April 1994). "Organization of the embryonic and early postnatal murine hippocampus. I. Immunocytochemical characterization of neuronal populations in the subplate and marginal zone". The Journal of Comparative Neurology 342 (4): 571–95. doi:10.1002/cne.903420406. PMID 7913715.
- Drakew A, Frotscher M, Deller T, Ogawa M, Heimrich B (February 1998). "Developmental distribution of a reeler gene-related antigen in the rat hippocampal formation visualized by CR-50 immunocytochemistry". Neuroscience 82 (4): 1079–86. doi:10.1016/S0306-4522(97)00326-6. PMID 9466431.
- Alcántara S, Ruiz M, D'Arcangelo G et al. (October 1998). "Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse". The Journal of Neuroscience 18 (19): 7779–99. PMID 9742148.
- D'Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T (January 1997). "Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody". The Journal of Neuroscience 17 (1): 23–31. PMID 8987733.
- Ogawa M, Miyata T, Nakajima K et al. (May 1995). "The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons". Neuron 14 (5): 899–912. doi:10.1016/0896-6273(95)90329-1. PMID 7748558.
- Meyer G, Goffinet AM, Fairén A (December 1999). "What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex". Cerebral Cortex 9 (8): 765–75. doi:10.1093/cercor/9.8.765. PMID 10600995.
- Meyer G, Soria JM, Martínez-Galán JR, Martín-Clemente B, Fairén A (August 1998). "Different origins and developmental histories of transient neurons in the marginal zone of the fetal and neonatal rat cortex". The Journal of Comparative Neurology 397 (4): 493–518. doi:10.1002/(SICI)1096-9861(19980810)397:4<493::AID-CNE4>3.0.CO;2-X. PMID 9699912.
- Bielle F, Griveau A, Narboux-Nême N et al. (August 2005). "Multiple origins of Cajal-Retzius cells at the borders of the developing pallium". Nature Neuroscience 8 (8): 1002–12. doi:10.1038/nn1511. PMID 16041369.
- Takiguchi-Hayashi K, Sekiguchi M, Ashigaki S et al. (March 2004). "Generation of reelin-positive marginal zone cells from the caudomedial wall of telencephalic vesicles". The Journal of Neuroscience 24 (9): 2286–95. doi:10.1523/JNEUROSCI.4671-03.2004. PMID 14999079.
- Lavdas AA, Grigoriou M, Pachnis V, Parnavelas JG (September 1999). "The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex". The Journal of Neuroscience 19 (18): 7881–8. PMID 10479690.
- Marin-Padilla M (1971). "Early prenatal ontogenesis of the cerebral cortex (neocortex) of the cat (Felis domestica). A Golgi study. I. The primordial neocortical organization". Zeitschrift Für Anatomie Und Entwicklungsgeschichte 134 (2): 117–45. doi:10.1007/BF00519296. PMID 4932608.
- Marin-Padilla M (1972). "Prenatal ontogenetic history of the principal neurons of the neocortex of the cat (Felis domestica). A Golgi study. II. Developmental differences and their significances". Zeitschrift Für Anatomie Und Entwicklungsgeschichte 136 (2): 125–42. doi:10.1007/BF00519174. PMID 5042754.
- García-Moreno F, López-Mascaraque L, De Carlos JA (January 2007). "Origins and migratory routes of murine Cajal-Retzius cells". The Journal of Comparative Neurology 500 (3): 419–32. doi:10.1002/cne.21128. PMID 17120279.
- Borrell V, Marín O (October 2006). "Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling". Nature Neuroscience 9 (10): 1284–93. doi:10.1038/nn1764. PMID 16964252.
- Sava BA, Dávid CS, Teissier A et al. (May 2010). "Electrophysiological and morphological properties of Cajal-Retzius cells with different ontogenetic origins". Neuroscience 167 (3): 724–34. doi:10.1016/j.neuroscience.2010.02.043. PMID 20188149.
- Hevner RF, Neogi T, Englund C, Daza RA, Fink A (March 2003). "Cajal-Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin". Brain Research. Developmental Brain Research 141 (1-2): 39–53. doi:10.1016/S0165-3806(02)00641-7. PMID 12644247.
- Imamoto K, Karasawa N, Isomura G, Nagatsu I (July 1994). "Cajal-Retzius neurons identified by GABA immunohistochemistry in layer I of the rat cerebral cortex". Neuroscience Research 20 (1): 101–5. doi:10.1016/0168-0102(94)90027-2. PMID 7984336.
- Ina A, Sugiyama M, Konno J et al. (August 2007). "Cajal-Retzius cells and subplate neurons differentially express vesicular glutamate transporters 1 and 2 during development of mouse cortex". The European Journal of Neuroscience 26 (3): 615–23. doi:10.1111/j.1460-9568.2007.05703.x. PMID 17651422.
- Janusonis S, Gluncic V, Rakic P (February 2004). "Early serotonergic projections to Cajal-Retzius cells: relevance for cortical development". The Journal of Neuroscience 24 (7): 1652–9. doi:10.1523/JNEUROSCI.4651-03.2004. PMID 14973240.
- Kilb W, Luhmann HJ (April 2001). "Spontaneous GABAergic postsynaptic currents in Cajal-Retzius cells in neonatal rat cerebral cortex". The European Journal of Neuroscience 13 (7): 1387–90. doi:10.1046/j.0953-816x.2001.01514.x. PMID 11298799.
- Kirmse K, Kirischuk S (April 2006). "Ambient GABA constrains the strength of GABAergic synapses at Cajal-Retzius cells in the developing visual cortex". The Journal of Neuroscience 26 (16): 4216–27. doi:10.1523/JNEUROSCI.0589-06.2006. PMID 16624942.
- Mienville JM (November 1998). "Persistent depolarizing action of GABA in rat Cajal-Retzius cells". The Journal of Physiology 512 (Pt 3): 809–17. doi:10.1111/j.1469-7793.1998.809bd.x. PMC 2231241. PMID 9769423.
- Badea A, Nicholls PJ, Johnson GA, Wetsel WC (February 2007). "Neuroanatomical phenotypes in the reeler mouse". NeuroImage 34 (4): 1363–74. doi:10.1016/j.neuroimage.2006.09.053. PMC 1945208. PMID 17185001.
- Katsuyama Y, Terashima T (April 2009). "Developmental anatomy of reeler mutant mouse". Development, Growth & Differentiation 51 (3): 271–86. doi:10.1111/j.1440-169X.2009.01102.x. PMID 19379278.
- Folsom TD, Fatemi SH (May 2013). "The involvement of Reelin in neurodevelopmental disorders". Neuropharmacology 68: 122–35. doi:10.1016/j.neuropharm.2012.08.015. PMC 3632377. PMID 22981949.
- Baloyannis SJ (July 2005). "Morphological and morphometric alterations of Cajal-Retzius cells in early cases of Alzheimer's disease: a Golgi and electron microscope study". The International Journal of Neuroscience 115 (7): 965–80. doi:10.1080/00207450590901396. PMID 16051543.
- Lakatosova S, Ostatnikova D (September 2012). "Reelin and its complex involvement in brain development and function". The International Journal of Biochemistry & Cell Biology 44 (9): 1501–4. doi:10.1016/j.biocel.2012.06.002. PMID 22705982.
- Fatemi SH, Snow AV, Stary JM et al. (April 2005). "Reelin signaling is impaired in autism". Biological Psychiatry 57 (7): 777–87. doi:10.1016/j.biopsych.2004.12.018. PMID 15820235.
- Wynshaw-Boris A (October 2007). "Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development". Clinical Genetics 72 (4): 296–304. doi:10.1111/j.1399-0004.2007.00888.x. PMID 17850624.
- Kato M, Dobyns WB (April 2003). "Lissencephaly and the molecular basis of neuronal migration". Human Molecular Genetics 12 (Suppl 1): R89–96. doi:10.1093/hmg/ddg086. PMID 12668601.
- Blümcke I, Thom M, Wiestler OD (April 2002). "Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy". Brain Pathology 12 (2): 199–211. doi:10.1111/j.1750-3639.2002.tb00436.x. PMID 11958375.