<p> Cortical Interneurons are an incredibly diverse population of locally connecting GABAergic inhibitory neurons. In rodents, cortical interneurons originate from the ventral telencephalon during embryogenesis, and migrate tangentially into the neocortex following their specification. Despite our understanding of the early patterning of the telencephalon, established through sonic hedgehog (SHH), fibroblast growth factor (FGF) signaling, and wingless-int (WNT) we still know very little about the downstream effectors responsible for establishing interneuron diversity. This work has aimed to elucidate the role of secreted morphogens in interneuron specification, specifically FGF and WNT.</p><p> I began by investigating the role of FGF signaling in the specification of cortical interneurons by targeting downstream effectors, a critical adaptor protein, and receptors for FGF signaling. In particular, I examined the role of two candidate transcription factors classically found downstream of FGF: <i> Ets1</i> and <i>Ets2.</i> Previously identified by microarray as enriched in cortical interneurons at developmental timepoints, <i> Ets1</i> and <i>Ets2</i> single and double mutants had no obvious defects in interneuron specification as assessed by immunohistochemistry. Using both forebrain and interneuron specific <i>Cre</i> recombinase drivers, I also generated conditional knockouts of the adaptor protein <i> FRS2&alpha;,</i> which is critical for FGF signaling through the MAP kinase and PI3 kinase signaling pathways (Hadari <i>et al,</i> 2001). Interestingly, pan-forebrain loss of <i>FRS2&alpha;,</i> failed to replicate the phenotype of forebrain removal of <i>FGF receptors 1, 2</i> and <i>3.</i> Similarly, interneuron specific removal of <i>FRS2&alpha;,</i> did not affect interneuron migration or fate. Additionally, through a complex set of genetic crosses, I generated an interneuron specific triple knockout of <i>FGFRs 1, 2,</i> and <i>3;</i> this animal also did not exhibit any gross interneuron specification defects. These results together suggest that the development of cortical interneurons is likely not regulated by FGF signaling, at least not after their initial specification.</p><p> Previous work in the developing spinal cord has shown that cell identity can be conferred by exposure to diffusible morphogen gradients. Despite previous attempts, delineation of cell types by morphogen gradient in a "spinal cord" fashion has not yet been discovered in the forebrain. We have discovered a novel rostral-caudal regionality within the medial ganglionic eminence (MGE) that delineates the specification of the two main classes of cortical interneuron subtypes based on their exposure to a non-canonical WNT signaling gradient. Caudally located MGE progenitors receiving high levels of WNT signaling give rise to cortical interneurons labeled by somatostatin (SST). Parvalbumin (PV) expressing basket cells, in contrast, originate primarily from the most rostral region of the MGE, and do not signal highly through WNT pathways. Interestingly, canonical WNT signaling through &beta;-catenin is not required for this process. WNT signals transmitted via cleavage of the intracellular domain of the non-canonical WNT receptor RYK, however, are sufficient to drive interneuron progenitors to a SST fate.</p>

Elucidating the molecular mechanisms that guide and shape the development of nervous systems within the human body is paramount not only from the perspective of developmental biology, but also from a medical viewpoint concerning the palliative and curative treatment of congenital birth defects, as well as for engineering potential treatments for degenerative diseases. Our focus was to first study a relatively simple model of nervous system development and then progress to a more complex system for analysis The sympathetic nervous system (SNS), a subdivision of the peripheral nervous system (PNS), is a relatively simple system to study, particularly the development of the sympathetic chain ganglia (SCG). We sought to discover whether the powerful morphogen sonic hedgehog (Shh) is involved in the migration, patterning, or specification of the developing SNS. Our results indicate that Shh is essential for migration and patterning, but not for neural, glial, or catecholaminergic specification of the SNS We next studied the enteric nervous system (ENS) as a complex model of nervous system development. The ENS is the largest and most complex division of the PNS, containing many striking similarities to the brain. Recently, the basic helix-loop-helix (bHLH) transcription factor Hand2 has been shown to be involved in neuronal phenotype selection in embryos with a neural crest specific deletion of Hand2. Unfortunately, these embryos die due to cardiac defects by 12.5 dpc. By attempting two distinct methods to rescue Hand2 mutant embryos until birth, we were able to successfully analyze how the loss of Hand2 effects the development of the ENS. Our results demonstrate that Hand2 plays a key role in migration, patterning, neuronal and glial specification, as well as neuronal phenotype selection within the developing ENS Together, the studies of these two nervous systems add to the cumulative research and contribute toward the search for a complete understanding of nervous system development that is essential in the treatment of a number of congenital disorders affecting the PNS such as neuroblastoma, Hirschsprung's Disease, hyperganglionosis, and intestinal neuronal displaysia type B, as well as the in treatment of other diseases including hyperthyroidism, heart failure, chronic arterial hypertension, anxiety, and irritable bowel syndrome / acase@tulane.edu

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Almost 600,000 infants acquire human immunodeficiency virus (HIV) infection from their mothers each year, with the majority of these infants living in developing countries. Knowledge regarding the impact of maternal and infant (HIV) infections upon birthweight is controversial. Little is known regarding the presence of HIV infection upon concurrent growth in developing countries. Data from a cohort of HIV-positive and HIV-negative women and their infants in Kisumu, Kenya was analyzed to assess maternal and infant HIV status with birthweight, growth and mortality of the infants. Three hundred and seventy-nine infants were assessed for health at four week intervals for the first year of life. The results of the analyses suggest that although differences in birthweight by (HIV) status alone are not present, HIV-infected infants subsequently gain less weight in the first year of life. Lower weight gain and positive HIV-status were independent predictors of mortality.