Location:
Seminar Area Genetics

Abstract:
In East Asia, the ‘Acheulian-like’ handaxes were first discovered in 1978 in the Imjin Basin in central Korea. They are now known not only throughout Korea but also at many places in China and Vietnam. Statistical and technological evaluation of the Korean handaxes demonstrates their morphology is hardly different from those of the ‘west’. Although it is yet to be determined whether such similarity is the result of ‘cultural convergence’, which perhaps is not so, what is striking is the age for some ‘younger’ specimens. In the Imjin Basin, handaxes are found within deposits of probable early Middle Pleistocene age, but more often they are associated with the late Pleistocene deposits formed on top of the basalt plain. Grains of the Aira-Tanzawa tephra within the uppermost part of the deposit provides a secure date of c. 30 ka as their terminus ante quem. Their terminus post quem can be determined by the age of the basalt bedrock, and radiocarbon dating of a tree trunk captured by lava hints at the date of c. 50 to 40 ka. Full-blown Upper Palaeolithic industry with such refined tools as projectile points had appeared by >40 ka, thus, it could be that Korea during the OIS 3 had been occupied by at least two groups with very different technologies. In that regard, it is interesting to notice that archaic assemblages in China and Vietnam are usually found in isolated intermontane basins while contemporary assemblages in Mongolia and southern Siberia to the north are with definite Mousterian features. In sum, despite the paucity of fossil evidence, spatiotemporal distribution of archaeological data seems to suggest that ancient populations were able to find sanctuaries to compete with anatomically modern humans for a prolonged period after the arrival of the latter in the region.

Contact:
Viola Mittag
phone + 49 (0) 341 3550 500

E-mail: mittag[>>> Please replace the brackets with an AT sign! <<<]eva.mpg.de
Website: http://www.eva.mpg.de/genetics

Location:
Seminar Area Genetics

Abstract:
Mutations in the PCDH19 gene on chromosome X (Xp22.1) cause a female-limited epilepsy (PCDH19 Female Epilepsy, PCDH19-FE) that is frequently associated with intellectual disability and autism.
Epilepsy affects heterozygous females and spares hemizygous males, with the exception of few mosaic males. PCDH19 encodes for rotocadherin-19 (PCDH19) that is a calcium-dependent cell-adhesion molecule belonging to the non-clustered elta2-protocadherin subclass of the cadherin superfamily. PCDH19 has six conserved extracellular cadherin repeats, a transmembrane region and an intracellular C-terminus (CT). We found that PCDH19 is expressed at both excitatory and inhibitory synapses of hippocampal neurons and regulates neuronal excitability via two distinct mechanisms: by modulating GABAAR transmission at synapses and gene expression in the nucleus.
Our data indicate that PCDH19 CT interacts with the GABAAR alpha subunits; upon PCDH19 shRNA-mediated downregulation, GABAAR surface expression is reduced and fast GABAergic transmission impaired. Since PCDH19 expression increases throughout embryonic development and peaks in the first postnatal days when GABA signaling orchestrates neuronal migration and arborization, we downregulated PCDH19 via shRNA in utero electroporation in rat hippocampus. Consistently with an impairment of GABAergic transmission, PCDH19 downregulation during brain development affects the migration and morphological maturation of pyramidal neurons and increases rat’s seizure susceptibility.
In addition, upon sustained NMDAR activation, PCDH19 CT is cleaved by gamma sectetase and enters the nucleus. In the nucleus, PCDH19 CT associates with the CoREST complex and represses the transcription of immediate early genes (IEGs), which are key regulators of neuronal plasticity and excitability. Conversely, PCDH19 shRNA-mediated downregulation increases IEGs transcripts. Notably, PCDH19 cleavage occurs in vivo upon epileptogenic stimuli, as demonstrated by CT generation in hippocampal homogenates from mice that experienced pilocarpine induced-seizures. We hypothesize that PCDH19 cleavage might represents a homeostatic mechanism in response to strong neuronal activation that prevents IEGs overactivation.
Finally, we generated a conditional PCDH19 KO mouse model by using LoxP-Cre technology. Our preliminary data suggest that Cre-mediated PCDH19 inactivation is associated with an epileptic phenotype that we will investigate in detail with a focus on mosaic PCDH19 expression and its role on PCDH19-FE pathogenesis.
Altogether, PCDH19 emerges as a new GABAAR binding partner that controls GABAergic transmission and simultaneously exerts a homeostatic control of excitability via IEGs expression regulation, thus suggesting new pathogenic mechanisms for PCDH19-FE.


Contact:
Viola Mittag
phone + 49 (0) 341 3550 500

E-mail: mittag[>>> Please replace the brackets with an AT sign! <<<]eva.mpg.de
Website: http://www.eva.mpg.de/genetics