The research group of developmental defects of the cerebral cortex (Prof. Dr. Angela Kaindl)
The research projects are
- primary autosomal recessive microcephaly
- perinatal brain damage
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Developmental disorders of the cerebral cortex
The formation of the mammalian cerebral cortex requires a strictly regulated developmental program determining cell proliferation, differentiation and an orchestrated movement of cells arising from different regions within the brain and born at different times to achieve a specific laminar position, orientation and connections with other cells.
Disorders of cerebral cortical development
Disorders of cerebral cortical development are an important cause of long-term morbidity in humans. We are interested in understanding how specific genetic defects and environmental impacts influence developmental events of the cortex and thereby contribute to the damage of the immature brain.
Fig. 1. Cerebral cortex formation involves progenitor cell divisions, which can be symmetrical (increase of progenitor pool) and asymmetric (production of committed precursors). Progenitors give rise to various cell types such as neurons and glial cells (astrocytes, oligodendrocytes, microglia) that further differentiate/ mature and migrate. The cortical size depends not only on the generation, maturation and migration of cells, but also on the survival of generated cells (modified from link to Kaindl, Passemard et al. 2009)
The molecular mechanisms through which cyclin dependent kinase 5 regulatory associated protein 2 (CDK5RAP2, Figure 2) gene mutations lead to microcephaly in humans. The clinical and genetic characterization of patients with MCPH.
Primary autosomal recessive microcephaly
Table 1. Overview of MCPH genes
Cyclin dependent kinase 5 regulatory associated protein 2
Abnormal spindle-like, microcephaly associated
Centromeric protein J CENPJ
SCL/TAL1 interrupting locus
Perinatal brain damage
A second major focus of the group is the study of the role of microglia in the evolution of perinatal brain damage. Perinatal brain damage is a major contributor to mortality and morbidity of infants, leading often to mental retardation and sensory-motor impairment. The disease process is believed to be caused, sustained and aggravated by multiple perinatal factors that team up in a multi-hit fashion.
Clinical, epidemiological and experimental studies have unraveled some key factors such as inflammation, excitotoxicity and oxidative stress that contribute considerably to white and gray matter injury of the particularly susceptible brain of the premature infant. In these processes, microglia, the immune cells of the central nervous system (CNS), play a pivotal role. 'Surveying' (resting) microglia constantly screen the CNS and can be activated rapidly through various environmental changes and thereby contribute both to tissue damage and tissue restoration. The exact mechanisms that drive microglia into a damaging or a protective phenotype are still unknown (Figure 3).