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Abstract
Laminin α2 gene (LAMA2)-related Congenital Muscular Dystrophy (CMD) was distinguished by a defining central nervous system (CNS) abnormality—aberrant white matter signals by MRI—when first described in the 1990s. In the past 25 years, researchers and clinicians have expanded our knowledge of brain involvement in LAMA2-related CMD, also known as Congenital Muscular Dystrophy Type 1A (MDC1A). Neurological changes in MDC1A can be structural, including lissencephaly and agyria, as well as functional, including epilepsy and intellectual disability. Mouse models of MDC1A include both spontaneous and targeted LAMA2 mutations and range from a partial loss of LAMA2 function (e.g., dy2J/dy2J), to a complete loss of LAMA2 expression (dy3K/dy3K). Diverse cellular and molecular changes have been reported in the brains of MDC1A mouse models, including blood-brain barrier dysfunction, altered neuro- and gliogenesis, changes in synaptic plasticity, and decreased myelination, providing mechanistic insight into potential neurological dysfunction in MDC1A. In this review article, we discuss selected studies that illustrate the potential scope and complexity of disturbances in brain development in MDC1A, and as well as highlight mechanistic insights that are emerging from mouse models.
Highlights
Laminin Structure and FunctionLaminins are developmentally regulated extracellular matrix (ECM) molecules comprised of α, β, and γ chains
The dynamic expression pattern of laminin-α2 associated with synapses and dendrites suggests its likely role in synaptogenesis and/or synaptic plasticity (Anderson et al, 2005), both of which could contribute to a subset of the central nervous system (CNS) deficits seen in MDC1A patients, such as a high incidence of epilepsy
In the developing rat hippocampus, lamininα2 immunoreactivity increases during synaptogenesis, and upon a cortical lesion, which results in denervation and subsequent reinnervation, laminin-α2 immunoreactivity closely corresponds to the immunolabeling of the synaptic marker synaptophysin (Tian et al, 1997). These findings suggest that an α2-containing laminin has roles in synaptogenesis and synaptic plasticity, which we will discuss ahead when describing synaptic plasticity deficits in an MDC1A mouse model
Summary
Laminin Structure and FunctionLaminins are developmentally regulated extracellular matrix (ECM) molecules comprised of α, β, and γ chains. The ability of receptors to interact with α2-containing laminins is critical in the CNS, where the loss of laminin-α2 results in brain abnormalities that include neuronal migration defects that can result in lissencephaly.
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