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

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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)

Specifically addressing

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

A major interest of our team is to understand the molecular mechanisms underlying autosomal recessive primary microcephaly (MCPH). Microcephaly is a condition defined as a small cranium with a significantly reduced occipito-frontal head circumference. Microcephaly can be acquired (caused by environmental factors) or hereditary in origin and can become apparent congenitally (primary microcephaly) or postnatally (secondary microcephaly). MCPH is a genetically and clinically heterogeneous disease (Table 1, Kaindl, Passemard et al. 2009), and patients present typically with congenital microcephaly and mental retardation. Their microcephaly is a consequence of a reduced brain volume, which is evident particularly within the cerebral cortex and thus results to a large part from a reduction of grey matter. Some patients with MCPH further provide evidence of neuronal heterotopias, polymicrogyria or cortical dysplasia suggesting an associated neuronal migration defect. The molecular mechanisms and the phenotype spectrum of MCPH are not known in detail.

Table 1. Overview of MCPH genes

MCPH

Protein

Gene

Chromosome

 

MCPH1

Microcephalin

MCPH1

8p23

 

MCPH2

-

19q13.1-q13.2

   

MCPH3

Cyclin dependent kinase 5 regulatory associated protein 2

CDK5RAP2

9q33.3

 

MCPH4

-

15q15-q21

   

MCPH5

Abnormal spindle-like, microcephaly associated

ASPM

1q31

 

MCPH6

Centromeric protein J CENPJ

13q12.2

   

MCPH7

SCL/TAL1 interrupting locus

STIL 1p32

   

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).