LaMantia Lab - Research

Control of Gene Expression in the Developing and Adult Central Nervous System

 

Figure 1.

My research focuses on the central role of cell-cell signaling in establishing neuronal identity and connectivity in the mammalian forebrain. These events are key for constructing forebrain circuits that mediate sensation, movement, perception and cognition, and have emerged as likely targets for pathogenic processes that predispose individuals to psychiatric and neurological diseases. The primary observation that motivates this work was made in my laboratory in the mid-1990’s: we found that an essential dimension of mammalian forebrain induction (the early signaling between primordial embryonic tissues) and patterning (the establishment of domains of gene expression that prefigure subsequent local morphogenesis) is an adaptation of a cellular and molecular mechanism called non-axial mesenchymal/epithelial (M/E) induction that serves the same function in the developing limbs, heart, and craniofacial primordia. Most of the known cell biological and molecular determinants of M/E induction are shared at each site, and when these molecules are disrupted by pharmacological manipulation or genetic mutations, development at each site is compromised. These observations provide a strong foundation for a new approach to studying the molecular basis of morphogenesis and cell fate specification in the forebrain. In addition, they suggest new hypotheses for exploring the developmental basis of a wide range of brain diseases including schizophrenia and autism that often include craniofacial, limb or even cardiovascular anomalies among their endophenotypes.

The challenge that we now address is how this shared process is adapted to specify forebrain neural precursor (or “stem cells”) and constrain their subsequent maturation. To address this question, we are defining the critical portion of the genome that is central for mediating M/E induction at all sites, as well as specific genes that adapt the mechanism to the particular needs of neural versus musculoskeletal or vascular differentiation. In parallel, we ask how genes that establish vulnerability for schizophrenia, autism and other developmental disorders disrupt this process. Some forebrain inductive mechanisms resemble those that specify musculo-skeletal, vascular, odontogenic or cartilage differentiation; however, there is significant divergence. Moreover, the recognition that differentiation at each site—forebrain, limbs, heart and face—relies upon a singular developmental mechanism leads to a new hypothesis of developmental disorders that feature limb, cardiac and craniofacial anomalies as well as brain or behavioral disruptions as part of their range of symptoms. This spectrum of clinical features may reflect a common insult to non-axial M/E induction at an early time in development. The consequences would be seen as limb, heart and craniofacial dysmorphogenesis, and equivalent disruption of forebrain circuits. To evaluate this hypothesis, a portion of my work focuses upon molecular mechanisms that underlie a genomically determined developmental disorder: the 22q11 Deletion Syndrome (also known as DiGeorge or Velocardiofacial Syndrome) that features clinically significant limb, heart, and craniofacial dysmorphology as well as a forebrain phenotype: developmental delays early in life and a increased vulnerability for psychiatric diseases including schizophrenia during late adolescence and early adulthood.

Anthony LaMantia is co-author of Neuroscience (Sinauer & Associates, publisher), an introductory text of neurobiology for medical, graduate, and advanced undergraduate students.