The Role of AMOTL2 in the Development of the Cerebral Cortex – AMOTL2ND

The neocortex is a structure of the telencephalon responsible for complex cognitive processes such as attention, reasoning, emotions and feelings, thinking, memory, and consciousness. For the brain to function properly, different regions must communicate with each other through highly specialized cells—neurons. Within the neocortex, neurons are organized into six layers, generally divided into the upper layers (layers 2–4) and the deep layers (layers 5–6). Each cortical layer fulfills distinct functions, integrating information from the peripheral nervous system or enabling communication among brain regions within the same or opposite hemisphere. Consequently, the correct number of neurons in each layer, their identity, and their precise positioning must be tightly regulated. Indeed, disruptions to neuronal connectivity in the cortex underlie psychoneurological disorders such as autism and epilepsy.

The cerebral cortex develops through the process of corticogenesis, and all cortical neurons originate from a unique population of progenitor cells—radial glial cells (RGCs). These cells are highly polarized and extend their processes along the apical–basal axis of the cortex. Their apical processes attach to the ventricular surface of the developing brain, receiving signals transmitted via the cerebrospinal fluid, while their basal processes participate in the migration of newly generated neurons. This specific morphology of RGCs is determined by the presence of specific intercellular junction proteins and polarity-associated proteins exposed on their cell membrane. Proper RGC polarity is essential for receiving extracellular cues from the surrounding environment that regulate their proliferation and differentiation. The balance between these two processes is critical—dividing RGCs replenish their own pool, whereas their differentiation gives rise to neurons. Excessive RGC proliferation ultimately results in the generation of too many neurons, causing a condition known as megalencephaly. Conversely, premature differentiation of RGCs into neurons, which reduces the RGC population, leads to a decreased number of neurons and results in microcephaly.

Pathways involved in the regulation of RGC proliferation and differentiation include HIPPO/YAP and WNT/β-catenin signaling. Interestingly, one of the proteins modulating the activity of these pathways is AMOTL2 (angiomotin-like 2). However, its role has so far been investigated in physiological and pathophysiological contexts unrelated to the brain, such as embryonic development, blastocyst implantation, and angiogenesis. AMOTL2 belongs to the angiomotin family and was initially described as a scaffolding protein for intercellular junctions and a regulator of cell polarity. Considering AMOTL2’s central role in controlling structural organization, cell division, and polarity—processes that are critical for RGC physiology—it is justified to investigate the function of AMOTL2 in RGCs during corticogenesis.

The goals of the project are to thoroughly characterize AMOTL2 expression and function at various stages of corticogenesis, and to determine the impact of AMOTL2 gene deletion on both RGCs and mature neurons in the developing and adult cortex. The project will assess the influence of AMOTL2 on RGC adhesion, polarity, proliferative potential, and differentiation. It will also examine the activity of HIPPO/YAP and WNT/β-catenin signaling pathways under conditions of AMOTL2 gene deletion.

In summary, this project will be the first to investigate the role of AMOTL2 in corticogenesis and will shed new light on the mechanisms regulating the complex development of the central nervous system.