Human accelerated regions (HARs), first described in August 2006,[1][2] are a set of 49 segments of the human genome that are conserved throughout vertebrate evolution but are strikingly different in humans. They are named according to their degree of difference between humans and chimpanzees (HAR1 showing the largest degree of human-chimpanzee differences). Found by scanning through genomic databases of multiple species, some of these highly mutated areas may contribute to human-specific traits. Others may represent loss of function mutations, possibly due to the action of biased gene conversion [2][3] rather than adaptive evolution.
Several of the HARs encompass genes known to produce proteins important in neurodevelopment. HAR1 is an 106-base pair stretch found on the long arm of chromosome 20 overlapping with part of the RNA genes HAR1F and HAR1R. HAR1F is active in the developing human brain. The HAR1 sequence is found (and conserved) in chickens and chimpanzees but is not present in fish or frogs that have been studied. There are 18 base pair mutations different between humans and chimpanzees, far more than expected by its history of conservation.[1]
HAR2 includes HACNS1 a gene enhancer "that may have contributed to the evolution of the uniquely opposable human thumb, and possibly also modifications in the ankle or foot that allow humans to walk on two legs". Evidence to date shows that of the 110,000 gene enhancer sequences identified in the human genome, HACNS1 has undergone the most change during the evolution of humans following the split with the ancestors of chimpanzees.[4] The substitutions in HAR2 may have resulted in loss of binding sites for a repressor, possibly due to biased gene conversion [5] .[6]
n molecular biology, Human accelerated region 1 (highly accelerated region 1, HAR1) is a segment of the human genome found on the long arm of chromosome 20. It is a Human accelerated region. It is located within a pair of overlapping long non-coding RNA genes, HAR1A (HAR1F) and HAR1B (HAR1R).[1]
HAR1A[edit]
HAR1A was identified in August 2006 when human accelerated regions (HARs) were first investigated. These 49 regions represent parts of the human genome that differ significantly from highly conserved regions of our closest ancestors in terms of evolution. Many of the HARs are associated with genes known to play a role in neurodevelopment. One particularly altered region, HAR1, was found in a stretch of genome with no known protein-coding RNA sequences. Two RNA genes, HAR1F and HAR1R, were identified partly within the region. The RNA structure of HAR1A has been shown to be stable, with a secondary structure unlike those previously described.
HAR1A is active in the developing human brain between the 7th and 18th gestational weeks. It is found in the dorsal telencephalon in fetuses. In adult humans, it is found throughout the cerebellum and forebrain; it is also found in the testes.[1] There is evidence that HAR1 is repressed by REST in individuals with Huntington's disease, perhaps contributing to the neurodegeneration associated with the disease.[4]
Further work on the secondary structure of HAR1A has suggested that the human form adopts a different fold to that of other mammals exemplified by the chimpanzee sequence.[5]
HAR1B[edit]
The HAR1B gene overlaps HAR1A, and is located o
The term Cajal–Retzius cells (CR cells) has nowadays been used to identify an 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.
History[edit]
| Neuron: Cajal-Retzius Cell | |
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Cajal–Retzius cells as drawn by Santiago Ramón y Cajal in 1891
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| NeuroLex ID | nlx_cell_20081206 |
It all started in 1891 when the famous neuroscientist and Nobel laureate, Santiago Ramón y Cajal described slender horizontal bipolar cells he had found in an histological preparation of the developing marginal zone of lagomorphs.[1] 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.[2][3]
Later on in 1899, Cajal drew the neurons in layer I of the human fetus at term and newborn.[4] 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,[5][6][7] The cells different morphologies and the fact that Cajal and Retzius used different species in different times of development led to several reviews on the definition of the Cajal–Retzius cells.[8][9][10][11][12][13] In fact immunohistochemical studies performed at advanced developmental stages in human and macaque cortex visualize cells more similar to the cells Cajal described.[10][14] In contrast, studies of the human mid-gestation period describe cells closer to the Retzius type.[15]
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.[13][15][16][17] Various studies then proved the Cajal–Retzius cells as being responsible for the production of reelin,[17][18][19]
In 1999 Meyer loosely defined the Cajal–Retzius cells as the family of Reln-immunoreactive neurons in the marginal zone,[20] 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.[21] He also described simpler cells with simpler morphologies in the marginal zone of rodents.[20]
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.[22]
However, a clear classification scheme as so far not been established.[citation needed]
Developmental Origin[edit]
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 [22] the cortical hem [23] and retrobulbar ventricular zone.[22][24]
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.[22]
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,[25][26] 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.[27] 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.[28]
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 [22] 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.[29]
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.[22]
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.[12]
Properties and Functions[edit]
CR cells in rodents and primates are glutamatergic (using glutamate as a transmitter),[30] but a subpopulation of CR cells may beGABAergic(using GABA as a transmitter).[31]
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,[21] ionotropic and metabotropic glutamate receptors,[21] vesicular glutamate transporters,[32] and a number of different calcium-binding proteins, such as calbindin, calretinin and parvalbumin.[21] 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.[5]
CR cells receive an early serotonergic input, which in mice forms synaptic contacts.[33]
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).[34]
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.[35] Kirmse and Kirischuk [35] 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.[36]
A role in brain development[edit]
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).[5]
Neurodevelopmental Disorders[edit]
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 migrationand consequently, cytoarchitecture in the cerebellum, hippocampus and cerebral cortex,[5][37][38]
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.[5] 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.[37][39] The reeler mutant has been used, because of its characteristics, as a model for the study of neuropsychiatric disorders.[39]
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.[40]
Other diseases said to be related to Cajal–Retzius cells, especially with the production of reelin, are schizophrenia, bipolar disorder,autism, lissencephaly and temporal lobe epilepsy.
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. Actually, it has been discovered that abnormal brain lamination is one of the probable causes of schizophrenia.[39] Furthermore, it has been show that in schizophrenic’s brains, as well as in bipolar disorder’s, the glycoprotein reelin is 50% downregulated, which is associated to abnormal DNA methylation of the RELN gene promoter.[41] In Autism patient’s brains there are also structural abnormalities in the neocortex and levels of reelin are diminished, suggesting the involvement of CR cells in this disorder,[39][41][42]
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,[39] giving the brain a smooth appearance.[43] There are five genes related to lissencephaly, including LIS1, the first to be discovered, and RELN.[44] Apparently Cajal–Retzius cells aren’t affected in case of mutation in LIS1 gene,[43] even though the product of this gene interferes with reelin interaction with their receptors.[39] 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.[43]
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.[45]