A number of the human genes implicated in primary microcephaly encode proteins involved in the spindle assembly checkpoint (SAC) process or components of centrosomes (the major type of microtubule-organizing center in animals). Each centrosome is composed of two centrioles; centrioles have two main functions: organization of the mitotic/meiotic spindle apparatus and organization of flagella and cilia. In most cases of hereditary microcephaly, the pathogenic variants are partial loss-of-function mutations.
See the human disease model report 'microcephaly, primary' (FBhh0000325) for additional information and a listing of microcephaly subtypes modeled in Drosophila.
In multiple systems, including flies, it has been found that results of spindle defects differ significantly depending on the stage of development and the tissue involved. Lack of centrosomes does not prevent spindle assembly, but spindle assembly is inefficient and accuracy of chromosome segregation may be compromised. The spindle assembly checkpoint is also not essential for cell division; it has been postulated that it may be more critical for tissues in which the cell division plane is important.
In Drosophila, animals homozygous for loss-of-function mutations in the gene mad2, which a encodes conserved component of the spindle assembly checkpoint, appear to develop normally and are fertile. The primary mutant phenotype is failure to undergo mitotic arrest in response to spindle damage induced by colchicine treatment. RNAi-effected reduction in mad2 expression results in shortened mitoses and gives less time to correct any chromosome misorientation at metaphase II, resulting in a significantly higher rate of chromosome segregation errors.
Mutations of the Drosophila Sas-4 gene, which encodes a component of centrioles, have also been characterized. Animals homozygous for loss-of-function alleles survive to adulthood, but die within days of eclosion. In imaginal discs, compensatory proliferation to counteract cell loss is observed. Many of the defects observed in adults can be explained by lack of cilia.
A fly model of microcephaly that combines mutations of these two genes has been developed. Although mad2 or Sas-4 single mutants survive to adulthood, double mutants die at the larval-pupal transition. Assaying effects on the larval brain, mad2 Sas-4 double mutants show highly elevated apoptosis, leading to increased cell death, reductions in the neural progenitor pool, and disruption of brain development; the brain is significantly reduced in size.
Additional combinations that include one gene affecting the SAC and a second gene affecting centrosomes have been characterized with similar results:
mad2 with asl (which encodes a component of the centriole); mad2 with cnn (which encodes a component of the centrosome); Mad1 (which encodes a component of the spindle checkpoint) with Sas-4. The human ortholog of Dmel\Sas-4, CENPJ, is implicated in microcephaly 6 (MIM:609279; FBhh0000777). The human ortholog of Dmel\cnn, CDK5RAP2, is implicated in microcephaly 3 (MIM:608201; FBhh0000781).
In the mad2 Sas-4 double mutant system, neural cells appear to be more tolerant of depletion of both centrosomes and the SAC than epithelial cells. In the wing discs of double mutant animals, much higher levels of cell death are observed, leading to a complete loss of imaginal discs. It is postulated that this is due to increased tolerance of aneuploidy in neural cells. Alternatively, it may be explained by differences in response of tissues with organization dependent upon different aspects of cell division, such as asymmetric division or oriented cell division.
See related human disease model reports 'cancer, models of chromosomal instability' (FBhh0000763) and 'cancer, neural stem cell, centrosome dysfunction' (FBhh0000780).
[updated Mar. 2018 by FlyBase; FBrf0222196]
Primary microcephaly (MCPH) refers to the clinical finding of a head circumference less than 3 standard deviations below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation; additional clinical features may include short stature or mild seizures (review by Woods et al., 2005; pubmed:15806441). [from MIM:251200; 2016.06.16]
Lack of centrosomes does not prevent spindle assembly, but spindle assembly is inefficient and accuracy of chromosome segregation may be compromised (FBrf0235458 and references cited therein).
The spindle assembly checkpoint is also not essential for cell division; it has been postulated that it may be more critical for tissues in which the cell division plane is important (Patwardhan, et al., 2018; pubmed:29352115).
A number of the human genes implicated in primary microcephaly encode proteins that are involved in the spindle assembly checkpoint (SAC) or are components of centrosomes (Patwardhan, et al., 2018, pubmed:29352115; Alcantara and O'Driscoll, 2014, pubmed:24816482).
High-scoring ortholog of human MAD2L1 (1 Drosophila to 1 human). Dmel\mad2 shares 46% identity and 71% similarity with the human gene.
High-scoring ortholog of human CENPJ (1 Drosophila to 1 human); additional low-scoring orthologs in human. Dmel\Sas-4 shares 24% identity and 39% similarity with the human CENPJ gene.
Low-scoring ortholog of human CEP152 (1 Drosophila to 1 human). Dmel\asl shares 19% identity and 37% similarity with the human gene.
Low- to moderate-scoring ortholog of human CDK5RAP2; additional low-scoring orthologs in human (1 Drosophila to 3 human). Dmel\Sas-4 shares 19% identity and 34% similarity with the human CDK5RAP2 gene.
High-scoring ortholog of human MAD1L1 (1 Drosophila to 1 human). Dmel\Mad1 shares 25% identity and 47% similarity with the human gene.
