Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2014

2061  The University of Texas at San Antonio  (23621)

Principal Investigator: Gaufo, Gary

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 310,308

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 9/30/11 <> 7/31/16

Restricted Research: YES

Academic Discipline: BIOLOGY DEPARTMENT  

Department, Center, School, or Institute: UTSA Neurosciences Institute  

Title of Contract, Award, or Gift: Morphogen-dependent regulation of motor neurogenesis along the A/P axis

Name of Granting or Contracting Agency/Entity: National Institutes of Health

Program Title: none
CFDA Linked: Extramural Research Programs in the Neurosciences and Neurological Disorders


Coordination of neurogenesis along the major axes of the neural tube is essential for establishing the complex circuitry of the adult brain and spinal cord. Via a concentration and temporal dependent mechanism, the morphogen Sonic hedgehog (Shh) controls the sequential generation of different neuronal subtypes in the ventral neural tube. This function of Shh along dorsoventral (DV) axis is established, but its contribution along the anteroposterior (AP) axis is unknown. Our preliminary results in the mouse embryo show that Shh expression is graded along the length of the floor plate and is inversely proportional to its expression in the underlying notochord. This observation suggests that Shh from these principle signaling centers may contribute to ventral patterning differently along the AP axis. Indeed, our preliminary results show that conditional elimination of Shh in the floor plate, but not in the notochord, show that ventral patterning in the hindbrain is dramatically impaired compared to the spinal cord. We further show that conditional expression (gain-of-function) of activated Smo, an effector of Shh, in Shh floor plate-deficient embryos could rescue the ventral patterning defects along the AP axis in a temporal-dependent manner. Based on these preliminary results, we hypothesize that the different sensitivity and responsiveness of ventral progenitors in hindbrain and spinal cord to Shh contribute to a mechanism that controls the timely progression of neurogenesis along the AP axis. The aim of this proposal is to define the effector molecules that mediate the regional functions of Shh, and to determine the temporal requirement of Shh in ventral neurogenesis in the hindbrain and spinal cord. The first aim will further explore our Shh floor plate-deficient genetic mouse model to identify the Gli transcription factor(s) deployed by Smo in Shh floor plate-deficient, rescued embryos. The second aim will test the temporal requirement of Shh on the onset and termination of ventral neurogenesis in the hindbrain and spinal cord. We will use a conditional approach to temporally eliminate Shh function in the floor plate and notochord at different stages of neurogenesis. Our proposal will help define the role for Shh in ventral neurogenesis along the AP axis, and provide a conceptual framework by which other morphogens classically associated with DV patterning may also control neurogenesis along the AP axis.

Discussion: No discussion notes


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