Gyrencephaly (the folding of the surface of the neocortex) is a mammalian-specific trait present in almost all mammalian orders. Despite the widespread appearance of the trait, little is known about the mechanism of its genesis or its adaptive significance. Still, most of the hypotheses proposed concentrated on the pattern of connectivity of mature neurons as main components of gyri formation. Recent work on embryonic neurogenesis in several species of mammals revealed different progenitor and stem cells and their neurogenic potential as having important roles in the process of gyrification. Studies in the field of comparative neurogenesis revealed that gyrencephaly is an evolutionarily labile trait, and that some species underwent a secondary loss of a convoluted brain surface and thus reverted to a more ancient form, a less folded brain surface (lissencephaly). This phenotypic reversion provides an excellent system for understanding the phenomenon of secondary loss. In this review, we will outline the theory behind secondary loss and, as specific examples, present species that have undergone this transition with respect to neocortical folding. We will also discuss different possible pathways for obtaining (or losing) gyri. Finally, we will explore the potential adaptive consequence of gyrencephaly relative to lissencephaly and vice versa.

The human neocortex is a highly sophisticated and organized brain structure that is thought to mediate some of the most complex cognitive functions in humans including language and abstract thought. As such, environmental and genetic insults to its normal structure or function can result in devastating neurological conditions including severe epilepsy and intellectual disability. Malformations of cortical development are an increasing collection of disorders that cause neocortical abnormalities due to impaired developmental processes. One recently identified disorder in this class is a thin lissencephaly variant (TLIS) associated with several mutations in the C-terminus death domain of the caspase-2 activation adaptor CRADD (also known as RAIDD). Beyond this, little is known about the mechanism underlying TLIS pathophysiology despite an increasing number of identified individuals suffering from it. In order to better understand this disorder, as well as the normal developmental mechanisms that are impaired in its pathogenesis, I have developed and characterized three murine models by introducing one of a number of different genetic perturbations associated with TLIS. These animal models show behavioral and biochemical abnormalities similar to those seen in human TLIS subjects. Focusing future studies on the developmental processes that underlie differences seen in these mouse models could greatly inform understanding of disease mechanism in humans and assist in the development in therapeutic interventions. My work presented in this dissertation thus effectively establishes a translationally relevant animal model of TLIS.

Pac1/LIS1, an essential tip tracking protein of the WD40 super family, is required to target cytoplasmic dynein to the plus ends of astral microtubules in budding yeast. Pac1/LIS1 protein is composed of two regions: a small coiled-coil domain and a highly conserved WD40 repeat domain. Because of in vivo data suggesting the motor domain of Dyn1 interacts with Pac1, I attempted to locate the region of Pac1/LIS1 essential for binding to Dyn1/HC by utilizing PCR-mediated site directed mutagenesis. PCR-generated site directed Pac1(S226P) mutant appears to bind Dyn1/HC, allowing it to localize to the microtubule plus ends; whereas, Pac1(H197R) and Pac1(D379H) mutants appear to disrupt motor localization. I further hypothesized that Dyn1/HC would bind to either the coiled-coil domain or the WD40 repeat domain. Using truncated Pac1 constructs, I have observed that neither the coiled-coil domain nor the WD40 repeat domain alone is sufficient to recruit Dyn1/DHC to the plus ends of the cytoplasmic microtubules. Additionally, if I dimerize the WD40 repeat domain with a GST fusion tag, I observed that Dyn1/HC colocalized with the truncation at the spindle pole bodies. This result indicates that Pac1 must dimerize with its coiled-coil domain prior to interacting with Dyn1/HC. Furthermore, the WD40 dimer, is unable to track microtubule plus-ends; indicating that the very N-terminus of Pac1 is important for other interactions responsible for recruiting the Pac1/Dyn1 complex to the astral microtubule plus end.

Gyrencephaly (the folding of the surface of the neocortex) is a mammalian-specific trait present in almost all mammalian orders. Despite the widespread appearance of the trait, little is known about the mechanism of its genesis or its adaptive significance. Still, most of the hypotheses proposed concentrated on the pattern of connectivity of mature neurons as main components of gyri formation. Recent work on embryonic neurogenesis in several species of mammals revealed different progenitor and stem cells and their neurogenic potential as having important roles in the process of gyrification. Studies in the field of comparative neurogenesis revealed that gyrencephaly is an evolutionarily labile trait, and that some species underwent a secondary loss of a convoluted brain surface and thus reverted to a more ancient form, a less folded brain surface (lissencephaly). This phenotypic reversion provides an excellent system for understanding the phenomenon of secondary loss. In this review, we will outline the theory behind secondary loss and, as specific examples, present species that have undergone this transition with respect to neocortical folding. We will also discuss different possible pathways for obtaining (or losing) gyri. Finally, we will explore the potential adaptive consequence of gyrencephaly relative to lissencephaly and vice versa.