Primary Microcephaly

 

Evolution and Brain size

A large brain is a defining feature of humans, and is the end point in evolutionary expansion in cerebral cortical size. In mammals there has been a thousand-fold increase in cortical surface area between mouse and man. How has this come about? Clearly, genes controlling brain size must have experienced adaptive Darwinian changes, leading to altered protein function, enabling brain size to increase. Identifying these genes and understanding how the proteins' functions have altered over evolution is an important challenge.

 

 

 

 

Cellular Functions of Microcephalin

Cell Cycle: regulating chromosome condensation

In collaboration with Heidemarie Neitzel (Berlin) we have implicated microcephalin in the regulation of chromosome condensation/ organisation (AJHG 75:261, 2004). Chromosome studies on patients with microcephalin mutations reveal an unusual cellular phenotype. 10% of cells have a 'prophase-like' appearance, with highly condensed chromosomes in an intact nuclear envelope (LEFT). These are the consequence of early onset of chromosome condensation in the G2 phase of the cell cycle and of delayed decondensation post-mitosis.

 

DNA Damage Repair Signalling

With Penny Jeggo and Mark O'Driscoll, we have established that Microcephalin is a downstream component in the ATR signalling pathway, directly interacting with Chk1, and regulating G2/M through cdc25A (Nat Cell Biol 8 725). This links Seckel syndrome, another Microcephaly syndrome with Microcephalin, suggesting that further components of this pathway may also cause Microcephaly with short stature. This work also suggested a mechanism for premature chromosome condensation, as Microcephalin appears to be required for inhibitory phosphorylation of Cdk1 in S/G2 cell cycle phases.

 

Current Work

Currently we are working to further elucidate the cellular functions of microcephalin, particularly in cell cycle regulation, and its role in brain development, with the long term aim of establishing the functional significance of adaptive evolutionary changes in the protein.

 

 

 

 

Themes

• Disorders of Human Brain Size:
  Primary Microcephaly
  Primordial Dwarfism
  

• Autoimmune Disease of the Brain
  Aicardi Goutieres Syndrome
  

Other Links

Research Study Information
Laboratory Publications

 

 

Cellular Determinants of Brain Size

Brain volume reflects the number of cells generated during neurogenesis, balanced against the significant amount of apoptosis known to occur during brain development. Regulators of brain size are therefore likely to be proteins involved in the mechanics of cell cycle, or in the determination of cell death. The identification of five human disease genes, Microcephalin, ASPM, CDK5RAP2, CENPJ and STIL promise to make inroads into understanding regulation of brain size and its relationship to evolution.

 

Primary Microcephaly

A disorder of human brain size Loss of function mutations in Microcephalin, ASPM, CDK5RAP2, STIL and CENPJ lead to the human neurodevelopmental disorder, primary microcephaly. In this condition brain size is markedly reduced to a size comparable to that of early hominids. Therefore this genetic disorder appears to recapitulate an earlier evolutionary state.

 

 

Microcephalin

We identified the first gene for primary microcephaly, microcephalin, in 2002 (AJHG 71:136). It is an 835 AA protein with homologies to BRCA1 and TOPBP1. It contains three BRCT domains. These domains bind phosphorylated proteins and are present in many DNA repair and cell cycle proteins. It is widely expressed in both fetal and adult tissues, and particularly at high levels in the proliferative ventricular zone from which the cerebral cortex is generated. Though initially its function was unknown, recently diverse functions have been identified.