Scientific Meetings

Unanswered Questions

Mutated MeCP2

Is mutated MeCP2 detrimental or merely hypofunctional?

Is mutated MECP2 unstable? If so, and if the mutated protein is partially functional, can stabilizing drugs be beneficial?

MeCP2 Function

Why is overexpression of MeCP2 toxic?

What are the roles of the MeCP2 isoform(s)?

Does MeCP2 function primarily as a repressor or are other roles (splicing, unknown roles) equally or more important?

Assuming MeCP2 does function as a repressor, is its action dynamic and activity-dependent so that genes can be dynamically repressed and released from repression, or is it more of a one-way street: a progressive tightening up of repression to prevent inappropriate expression that can eventually be toxic?

Does MeCP2 function differently in different neuronal cell types?

Are there particular neuronal cell types that are especially important for particular clinical features: e.g. seizures, respiratory symptoms, learning deficits?

Does MeCP2 function to maintain patterns of genomic imprinting?

Is MeCP2 differentially expressed in neuronal and glial subtypes?

What role does MeCP2 play in dendrite and synapse development and how does its dysfunction contribute to the Rett phenotype?

The biological functions of MeCP2 in the nervous system vs. the rest of the body; does CNS knockout of MeCP2 reproduce all symptoms of RTT?

What is the role of the immune system in RTT pathogenesis?

What are the fundamental molecular interactions between MeCP2 and chromatin? How do RTT-inducing mutations lead to the disease?

What proportion of neurons need to be 'wild-type' during the critical period of maturation/differentiation for this to proceed (relatively) normally? Can this be answered effectively in mouse, which seems to be less tolerant of mutation (or retention of mutant neurons) than human brain?

Deficits

Are neural circuits in Rett syndrome patients in fact largely intact?

Which deficits in neuronal function are cell-autonomous, which depend on complex network interactions? This bears importantly on the issue of the relationship between disease in hemizygous null males and Rett syndrome patients (or heterozygous mice).

Do neurosecretory defects in Mecp2 null mice affect all or a subset of neurotransmitter & neurohormonal systems? What are the consequences for synaptic function? What are the underlying mechanisms?

Reversal

How complete is the rescue of complex brain functions upon restoration of MeCP2 expression? How sure can we be about cognition deficits and network wiring?

Target Genes

What are the MeCP2 target genes?

Which are the confirmed and accepted primary and secondary targets of MeCP2?

What directs MeCP2 to downstream targets; is methylation sufficent?

Treatments

Phenotypic screening of known clinically approved drugs in an animal model of a disease is a viable drug discovery option that is distinctly different than the biology driven mechanistic approach. The phenotypic approach capitalizes on the frequent finding of multiple activities in known drugs and the a priori unpredictable nature of phenotypic screening results. Is this an approach that should be implemented for Rett?

Are there treatments that can now be seriously considered in animal models as a prelude to clinical trials?

Could a normal Mecp2 allele on the inactive X chromosome be activated? What is the current state of understanding in this field?