Sažetak sa skupa
https://doi.org/10.21857/ypn4oc4189
The role of the extracellular matrix in neurodevelopmental brain disorders: a genetic perspective
Natasa Jovanov Milosevic
orcid.org/0000-0001-7897-6212
; Department of Biology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
*
Mihaela Bobic Rasonja
; Department of Biology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
Sara Trnski Levak
orcid.org/0000-0001-7737-0622
; Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
Ivona Kirchbaum
orcid.org/0009-0000-6591-1866
; Department of Biology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
* Dopisni autor.
Sažetak
The fetal cerebral wall is rich in extracellular matrix molecules (ECM) that fill the intercellular space, estimated to comprise up to 60% of the volume of the early fetal brain. Four numerous families of ECM molecules (hyaluronan, proteoglycans, glycoproteins, and link proteins) are the main components of the biochemical niches that mediate the distribution of key signaling and trophic factors during prenatal development and build mechanical scaffolds to conduct actively morphogenetic processes such as cell proliferation, migration, axon pathfinding, and cortical folding. The transient fetal zones, such as the marginal zone, subplate, and early intermediate zone, are rich in hydrated extracellular matrix (ECM), and the last two are the bases of the cortical (hyperintensity) pattern on MRI scans, highlighting the importance of ECM in brain diagnostic and prognostic MRI follow-up in fetuses. In collaboration with their receptor, the ECM components also play a significant role in the differentiation of dendrites and the genesis of spines and synapses. Finally, some ECM molecules become integral to the quadripartite synapse and perineuronal nets, contributing to the formation of the functional connectome. Humans have more ECM in the cortical wall during fetal development compared to the evolutionary closest primate species. This supports the ECM as an evolutionary force, in conjunction with prolonged brain development, which facilitates the formation of more synapses and more elaborate, complex connections, while also being an additional substrate for vulnerability and plasticity in humans. Mutation of ECM coding genes or dysregulations of the ECM molecules’ expression spatial and temporal patterns, can affect the processes of cell proliferation, migration, cortical folding, or differentiation, leading to a heterogeneous group of disorders- known as malformations of cortical development (MCD, such as microcephalia, megalocephalia, lissencephaly, polymicrogyria, periventricular nodular or subcortical band heterotopia), or neurodevelopmental disorders (NDD), such as epilepsy, autism spectrum (AS), schizophrenia, and/or intellectual disabilities (ID). With the latest advances in sequencing technologies, greater accessibility to whole-genome and whole-exome sequencing (WGS, WES) for diagnostic purposes has led to an increase in the number of mutated genes coding for ECM components identified in patients and linked to MCD or NDD. A few examples include mutations in the heparan sulfate proteoglycan 2 (HSPG2) and laminin subunit gamma 1 (LAMC1) genes, which are associated with disrupted proliferation in the ventricular and subventricular zones, leading to microcephaly, hemimegalencephaly, or focal cortical dysplasia. The mutations in genes coding glycoprotein reelin, ECM glycosylation enzymes, O-mannosyltransferase enzyme, and glycosyltransferase-like protein, or the adhesion G—protein-coupled receptor (RELN, POMT1, LARGE, and GPR56, respectively), have been found to hinder migration and cell adhesion, causing lissencephaly or cobblestone lissencephaly, bilateral frontoparietal polymicrogyria, or ID. Proteoglycans, including versican, neurocan, lumican, hyaluronan, and proteoglycan link protein-1, as well as collagens (encoded by VCAN, NCAN, LUM, HAPLN1, and COL4A1, respectively), are expressed in the subplate and marginal zone. When mutated or dysregulated, these proteins alter synaptogenesis and gyrification, resulting in MCD or ID. The genes PAX6, TBR1, SOX2, and MEF2C coding for transcription factors, as well as members of the Wnt and Notch signaling pathways, enzymes involved in DNA methylation and histone modifications, and miRNAs, regulate the quantity and distribution of the ECM and their dysregulation can be part of the pathogenesis of MCD and NDD. For example, the NDST1 and CHSY1 genes, which encode enzymes involved in ECM biosynthesis, are found to be mutated in patients with AS and IP (for additional examples, see Table 1). The new research paradigm, which leverages the potential of generating induced pluripotent stem cells from patients with MCD or NDD to cultivate cerebral organoids, is an exceptional tool for elucidating the function of ECM and its receptor genes in the developing brain, both in health and disease. Therefore, knowledge of the genetic basis of brain-specific ECM and its MRI representation contributes to understanding the pathogenesis of cortical malformations and brain function abnormalities, and has proven essential in identifying potential new targets for diagnostic and therapeutic approaches to treating neurodevelopmental disorders.
Ključne riječi
Hrčak ID:
333466
URI
Datum izdavanja:
25.6.2025.
Posjeta: 518 *