Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

Abstract

Microcephaly or reduced head circumference results from a multitude of abnormal developmental processes affecting brain growth and/or leading to brain atrophy. Autosomal recessive primary microcephaly (MCPH) is the prototype of isolated primary (congenital) microcephaly, affecting predominantly the cerebral cortex. For MCPH, an accelerating number of mutated genes emerge annually, and they are involved in crucial steps of neurogenesis. In this review article, we provide a deeper look into the microcephalic MCPH brain. We explore cytoarchitecture focusing on the cerebral cortex and discuss diverse processes occurring at the level of neural progenitors, early generated and mature neurons, and glial cells. We aim to thereby give an overview of current knowledge in MCPH phenotype and normal brain growth.

Keywords: MCPH genes; animal models; brain; brain malformation; intellectual disability; microcephaly; neuronal differentiation.

FIGURE 1

Major roles of microcephaly primary hereditary (MCPH) proteins in brain development. The increased number of discovered MCPH proteins expands the pathomechanism spectrum to include several cellular components. Centrosome Functions: the proteins of this group regulate proper centrosomal functions to balance the transition between neural progenitor cell (NPC) proliferation and differentiation by controlling cell cycle progression and cell cycle exit fraction. Nuclear Envelope Integrity: the proteins of this group affect the proper spindle alignment and cell fate determinants during NPC proliferation and protect radial glial cell (RGC) nuclei from mechanical stress injury during INM. Kinetochore Structure: the proteins of this group assure the correct alignment of chromosomes during mitosis. Mitotic Spindle Dynamics: the proteins of this group regulate the spindle dynamics and cell division. Chromatin Structure: the proteins of this group regulate gene expression during neurogenesis and assure proper DNA damage repair. Cytokinesis: the proteins of this group regulate the terminal step in the cell cycle, which leads to a physical separation between the daughter cells. Autophagy: the proteins of this group facilitate the removal of cytosolic protein aggregates and maintain mitochondrial homeostasis. Intracellular trafficking: the proteins of this group control the cellular retrograde trafficking from the Golgi to the endoplasmic reticulum. Fatty Acid Metabolisms: the proteins of this group affect the postnatal neuronal morphogenesis, which requires a normal lipogenesis process. Ribosomal RNA Biogenesis: the proteins of this group regulate ribosomal RNA processing and affect primary cilia resorption. Please refer to (Table 1) for full protein names. *MCPH1 is also involved in chromatin structure. **CENPJ is also involved in kinetochore structure. ***LMNB1 and LMNB2 are also involved in mitotic spindle dynamics.

FIGURE 2

An illustrative figure demonstrating the pathway toward normal brain development. Minor defects at crucial steps in neurogenesis result in various neurodevelopmental disorders including MCPH. NPCs, neural progenitor cells; IPCs, intermediate progenitor cells; oRGCs, outer radial glial cells; MCPH, microcephaly primary hereditary.