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PROJECT 1: Origin and regulation of motor neuron identity in the hindbrain Gary O. Gaufo, UTSA Anne M. Moon, University of Utah Ruru Chen, UTSA Neurobiology.

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Presentation on theme: "PROJECT 1: Origin and regulation of motor neuron identity in the hindbrain Gary O. Gaufo, UTSA Anne M. Moon, University of Utah Ruru Chen, UTSA Neurobiology."— Presentation transcript:

1 PROJECT 1: Origin and regulation of motor neuron identity in the hindbrain Gary O. Gaufo, UTSA Anne M. Moon, University of Utah Ruru Chen, UTSA Neurobiology Program NINDS Specialized Neuroscience Research Program

2 Student Career & Collaboration postdoctoral fellow with A. Chan at Emory University developing nonhuman primate and mouse models of Huntington’s disease with an emphasis on stem cell biology Charles Wang advised Ruru on statistics, and continues imbedding duties Visceral sensory precursors Postganglionic precursors

3 SUMMARY Current Progress & Milestones SNRP Output: 6-7 papers; 1 funded R01; 2 ad hox NIH review sections Specific Aim 1. Characterize the migration, differentiation, and Hox requirement of neural crest-derived postganglionic motor neurons. 3 Published manuscripts Waardenburg Syndrome rescue (complete in Year 5) Specific aim 2: Determine the role of Hoxb1 in postmitotic facial branchial motor neurons. Manuscript draft written Specific aim 3. Determine role of Fgf8 and Fgfr1/2 on parasympathetic motor & sensory ganglia development (Gaufo & Moon). 1 Published manuscript Acquiring data for 2 nd manuscript (complete in Year 5)

4 Specific aim 2: Determine the role of Hoxb1 in postmitotic facial branchial motor neurons.

5 Germline loss of Hoxb1 results in transformation of r4 branchial motor neurons into r2-like branchial motor neurons Gaufo & Chen, Unpublished Data ControlHoxb1 -/- r4 r5 r6 FBMN r2 r3 Isl1 Phox2b Gata3 FBMN CBMN BMN CBMN TBMN BMN

6 Determine Hoxb1 function in postmitotic motor neurons Hoxb1 Isl1 Rhombomere 4 (r4) Hoxb1 Ventricular zone Marginal zone Facial branchial MN domain Dorsal Ventral Loss of Hoxb1 function & GFP reporter in facial branchial motor neurons Cre excises exons 1 & 2 in the Isl1 domain Hoxb1GFP Isl1 Cre Ex1 Gaufo & Chen, Unpublished Data BMN Progenitor Domain Postmitotic BMNs

7 Hoxb1 activity in postmitotic motor neurons is required for migration Control (Hoxb1 G/+ )Hoxb1 G/C ; Isl1 Cre/+ r4 r5 r6 FBM r2 r3 Hoxb1GFP r4 r5 r6 r4 r5 TBM FVM Gaufo & Chen, Unpublished Data anterior posterior

8 Summary: Hoxb1 restricts multi-potent postmitotic motor neuron pool toward a specific branchial motor neuron lineage r2 r3 r4 r5 r6 ba1 ba2 Control r2 r3 r4 r5 r6 ba1 ba2 Hoxb1 loss in postMNs TBMN FVMN FBMN Gaufo & Chen, Unpublished Data CBMN

9 Applying the basic principle of Hox gene function to disease Why do certain genetic diseases originate in specific tissue coordinates of the body?

10 Human genetic disorders: Waardenburg Syndrome (WS) & Hirschprung’s Disease Pax3 +/- or Sox10 +/- associated neural crest defects

11 Specific Aim 1. Characterize the migration, differentiation, & Hox requirement of neural crest-derived postganglionic motor neurons.

12 Boundary cap cells maintain integrity of the nervous system Neural Crest-Derived Boundary Cap Cells Pax3 Krox20Sox10 Krox20 Gaufo et al., Unpublished Data CNS-r4 PNS-VIIIg CNS-r4 PNS-VIIIg

13 Sox10 is required for the formation of boundary cap cells ControlSox10 -/- CNS-r4 PNS-VIIIg Sox10 Krox20 CNS-r4 PNS-VIIIg Gaufo et al., Unpublished Data

14 Abnormal migration in absence of boundary cap cells ControlSox10 -/- Tuj1 Isl1 CNS-r4 PNS-VIIIg CNS-r4 PNS-VIIIg Gaufo et al., Unpublished Data

15 Sensitivity of boundary cap cells to Pax3/Sox10 along the AP axis ControlPax3 +/- ; Sox10 +/- Tuj1 Isl1 CNS-r4 PNS-VIIIg CNS-r4 PNS-VIIIg Gaufo et al., Unpublished Data

16 Model for rescuing boundary cap cell defect in WS mouse model r3 r4ba2 r2ba1 r3 r4ba2 r2 ba1 r3 r4 r2ba1 ba2 Pax3 +/- Sox10 +/- deficient neural crest Change AP identity of Pax3 +/- Sox10 +/- deficient NC Sensory ganglion r2 NC-derived BC cell r4 NC-derived BC cell Gaufo et al., Unpublished Data

17 Strategy to transform identity of r4 neural crest-derived Pax3/Sox10-deficient boundary cap cells Prediction: change in r4 NC identity rescues BC-associated defect Cell autonomous loss of Hoxb1, Sox10, & Pax3 Pax3Cre Hoxb1 Sox10 1x 2x Gaufo et al., Unpublished Data

18 Hox-dependent rescue of boundary cap cell defect in WS mouse model Pax3 Cre/+ ; Sox10 F/+ ; Hoxb1 F/F ControlPax3 Cre/+ ; Sox10 F/+ Isl1 Tuj1 CNS-r4 PNS-VIIIg CNS-r4 PNS-VIIIg CNS-r4 PNS-VIIIg Gaufo et al., Unpublished Data

19 Prototype model for rescuing diseases w/ specific AP positional signatures r3 r4ba2 r2ba1 r3 r4ba2 r2 ba1 r3 r4 r2ba1 ba2 Pax3 +/- Sox10 +/- deficient neural crest Change AP identity of Pax3 +/- Sox10 +/- deficient NC Sensory ganglion r2 NC-derived BC cell r4 NC-derived BC cell Gaufo et al., Unpublished Data

20 Food for thought: Can the fate of pediatric medulloblastoma be altered? Pediatric Medulloblastoma Anterior Posterior Dorsal Ventral Modified from Hedgehog Signaling Defect

21 ACKNOWLEDGEMENTS Former Members Ruru Chen, PhD Masumi Takano-Maruyama, PhD Karen Kao Current Members Meizhen Chen, PhD Oscar Trevino Angela Huang Neurosciences UTSA (Charlie, Salma, & Greg) SNRPhriday Group Image Analysis (Colleen) & Statistical Cores (DJ) funded by… NIH-NINDS, NIH-NIA, Whitehall Foundation, & SALSI


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