Proteomic analyses in early brain development and neuropathological implications of fetal growth restriction

Proteins are the primary functional units within cells, driving complex biological processes essential for stem cell differentiation into specific neural lineages and for the structural and functional maturation of the central nervous system. Advances in high-throughput proteomic technologies allow comprehensive profiling of molecular landscape of the brain, revealing dynamic, region- and time-specific changes in protein expression. During early embryonic development, pluripotency-associated proteins are highly expressed but gradually decline as lineage-specific markers and pathways governing DNA regulation and cytoskeletal organization become predominant. In fetal and postnatal stages, synaptic and metabolic proteins are enriched in a region-specific manner, reflecting functional compartmentalization and specialization in the central nervous system. Fetal growth restriction is an obstetric complication caused by sustained periods of inadequate oxygen and nutrient supply, preventing the fetus from achieving its genetic growth potential. Proteomic analysis of fetal tissues and biofluids has deepened our understanding of the molecular mechanisms associated with fetal growth restriction, highlighting metabolic and vascular adaptations, inflammatory responses and redox imbalances. These analyses have also uncovered molecular signatures with potential value as biomarkers for clinical diagnosis (e.g., complement proteins in maternal blood in fetal growth restriction), and prognosis (e.g., neurogenic locus notch homolog protein 1 as a modulator of fetal growth restriction response). Despite such advances, animal models remain indispensable for elucidating the multifactorial nature of fetal growth restriction-related neuropathology, pinpointing region-specific alterations. They also offer a controlled setting to explore how factors such as sex, gestational age at birth, and birth weight influence the impact of fetal growth restriction on brain development. A deeper understanding of neurodevelopmental processes and the pathological mechanisms involved in fetal growth restriction is critical for the development of effective diagnostic strategies and targeted therapeutic interventions. The purpose of this review is to provide synthesis of neuroproteomic alterations across developmental stages, highlighting how chronic intrauterine oxygen and nutrient deprivation, in humans and animals, shapes the proteomic landscape.