Implication of the golgi apparatus secretory functions in the developpement Of postnatal microcephaly and intellectual disabilities – MicroGol

Intellectual disability (ID, formerly called mental retardation) is an extremely stigmatizing condition characterized by limitations in cognitive, language and social abilities. It is estimated to involve more than 2% of the general population and requires the extensive use of public health resources. Primary Microcephaly (PM, i.e. insufficient brain size and volume) is a major cause of ID and several genes whose loss of function results in brain growth defects with mild to severe ID have now been identified. Major findings from the last decade, especially in the field of Primary Hereditary Microcephaly (MCPH) have established that PM usually results from a lack of neural progenitors during embryogenesis, leading to the limited production of mature neurons and a subsequent reduction in cortical volume. However, growing evidence suggest that the white matter can also be affected in microcephaly. Therefore, the question arises as to the involvement of distressed mature axons and/or myelin-forming cells (oligodendrocytes) in the pathophysiology of microcephaly and ID, especially as myelinated axons constitute almost half the volume of the human brain. Very interestingly, a number of genes recently implicated in growth retardation syndromes associated with postnatal microcephaly and white matter defects have turned out to encode regulators of the Golgi-mediated secretory traffic machinery. This project brings together two complementary research groups with strong expertise in hereditary microcephaly and brain development (Team 1, Vincent El Ghouzzi) and in intracellular dynamics, especially Golgi trafficking and secretory mechanisms (Team 2, Franck Perez). Findings shared by the two groups indicate that Dyggve-Melchior-Clausen (DMC, MIM 223800) syndrome, a growth retardation disorder associated with progressive postnatal microcephaly, is caused by the deficiency of a ubiquitous Golgi protein that we have named Dymeclin (Dimitrov, 2009). Our recent data reveal that both Dym-/- mutant mice and DMC patients show a significant reduction of white matter volume associated with defects in the way the myelin sheath is wrapped, and a reduced thickness of myelinated axons (Dupuis, 2015). Moreover neurons display a fragmented Golgi apparatus, impaired trafficking capacities in between the endoplasmic reticulum and the cis-Golgi compartments (Dupuis, 2015) and a facilitation of long-term depression (LTD) induction. This suggests that defective secretory trafficking combined with hypomyelination leads to a weakening of synaptic transmission and that this mechanism could explain ID, speech difficulties and postnatal microcephaly. However, we do not know if the myelination defects observed are a consequence of the axonal injury or vice versa, or if trafficking within neurons and oligodendrocytes is independently affected. Furthermore, the consequences of such a defective anterograde transport on synaptic efficiency is completely unexplored. Using appropriate and innovative cell biology assays as well as stem cell systems developed by the consortium (Boncompain, 2012; Boncompain & Perez, 2013; Srivastava, 2013; Fukata, 2013), the MicroGoL project will take advantage of the Dymeclin deficient mouse model to carry out a functional exploration of the role of the secretory trafficking in postnatal brain growth and the link that we believe exists between the perturbation of this trafficking and the development of postnatal microcephaly. Investigating this link represents a novel approach in the field of microcephaly and may have important consequences for several other progressive diseases where white matter and axonal trafficking defects have been recently evidenced, including Alzheimer disease.

Boncompain et al, Nature Meth. 2012, 9: 493-8

Dimitrov et al, Hum Mol Genet. 2009, 18: 440-53

Dupuis et al, Hum Mol Genet. 2015, 24, 2771-2783.

Fukata et al, J Cell Biol. 2013, 202: 145-61

Srivastava et al, Stem Cells, 2013, 31: 652-665